Arylsulphonamides, pharmaceutical compositions containing these compounds and processes for preparing them

ABSTRACT

The invention relates to new arylsulphonamides of the formula ##STR1## (wherein A, B and R 1  to R 6  are as defined in claim 1, the enantiomers, the cis- and trans-isomers thereof where R 4  and R 5  together represent a carbon-carbon bond, and the addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable addition salts thereof with inorganic or organic bases, if R 6  represents a hydroxy group) which have useful pharmacological properties, particularly antithrombotic activities and thromboxane-mediating activities. Furthermore, the new compounds are also thromboxane antagonists (TRA) and thromboxane synthesis inhibitors (TSH). They also have an effect on PGE 2  production.

This is a division of application Ser. No. 08/154,647, filed Nov. 18,1993 now U.S. Pat. No. 5,426,119 which is a division of application Ser.No. 07/523,167 filed May 14, 1990 now U.S. Pat. No. 5,294,626.

The present invention relates to new arylsulphonamides of formula##STR2## the enantiomers thereof, the cis- and trans-isomers if R₄ andR₅ together represent a carbon-carbon bond, and the addition saltsthereof, more particularly for pharmaceutical use the physiologicallyacceptable salts of addition with organic or inorganic bases if R₆represents a hydroxy group, which have valuable pharmacologicalproperties, more particularly an antithrombotic activity. In addition,the new compounds are also thromboxane antagonists (TRA) and thromboxanesynthesis inhibitors (TSH) and thus inhibit the activities which aremediated by thromboxane. Furthermore they affect the production of PGE₂in the lungs and the production of PGD₂, PGE₂ and PGF₂α in humanthrombocytes.

The present invention thus relates to the new compounds of formula Iabove, the salts of addition thereof with organic or inorganic bases,and particularly for pharmaceutical use the physiologically acceptableaddition salts thereof, pharmaceutical compositions which contain thesecompounds and processes for preparing them.

In the above formula

R₁ represents a phenylalkyl, trialkylphenyl, tetramethylphenyl orpentamethylphenyl group, a thienyl group optionally substituted by ahalogen atom or an alkyl group, or a phenyl group which may bemono-substituted by a nitro group or mono- or disubstituted by a halogenatom or by an alkyl, trifluoromethyl or alkoxy group, the substituentsbeing identical or different,

R₂, R₄ and R₅, which may be identical or different, each represents ahydrogen atom or an alkyl group or

R₂ represents a hydrogen atom or an alkyl group and R₄ and R₅ togetherrepresent a carbon-carbon bond,

R₃ represents a pyridyl group optionally substituted by an alkyl group,

R₆ represents a hydroxy, alkoxy, amino, alkylamino or dialkylaminogroup,

A represents a group of formula ##STR3## wherein R₇ represents ahydrogen atom or an alkyl group,

R₈ represents a hydrogen atom or

R₇ and R₈ together represent a methylene or ethylene group and

X represents an alkyl-substituted imino group or an oxygen or sulphuratom, the --CHR₇ -- group being connected to the --NR₂ -- group, and

B represents a carbon-carbon bond or a straight-chained C₁₋₄ alkylenegroup optionally substituted by one or two alkyl groups, whilst all thealkyl and alkoxy moieties mentioned hereinbefore may each contain 1 to 3carbon atoms.

As examples of the definitions given for the groups hereinbefore:

R₁ may represent a benzyl, 2-phenylethyl, 3-phenylpropyl,2,4,6-trimethylphenyl, 2,4,6-triethylphenyl, 2,4,6-tri-n-propylphenyl,2,3,5,6-tetramethylphenyl, 3,4,5,6-tetramethylphenyl,2,4,5,6-tetramethylphenyl, 2,3,4,5,6-pentamethylphenyl, 2-thienyl,3-thienyl, 5-methyl-2-thienyl, 5-ethyl-2-thienyl, 5-n-propyl-2-thienyl,5-n-isopropyl-2-thienyl, 5-chloro-2-thienyl, 5-bromo-2-thienyl,5-methyl-3-thienyl, 5-ethyl-3-thienyl, 5-n-propyl-3-thienyl,5-n-isopropyl-3-thienyl, 5-chloro-3-thienyl, 5-bromo-3-thienyl, phenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl,4-n-propoxyphenyl, 4-isopropoxyphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 4-nitrophenyl,3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,4-dibromophenyl,2,4-ditrifluoromethylphenyl, 2-methoxy-5-chlorophenyl or2-methyl-5-chlorophenyl group,

R₂, R₄, R₇ and R₈ may each represent a hydrogen atom, a methyl, ethyl,n-propyl or isopropyl group,

R₆ may represent a hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy,amino, methylamino, ethylamino, isopropylamino, dimethylamino,diethylamino, diisopropylamino or methyl-ethylamino group,

R₃ may represent a 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-methyl-pyrid-2-yl,2-methyl-pyrid-3-yl, 2-methyl-pyrid-4-yl or 6-isopropyl-pyrid-2-ylgroup,

X may represent an oxygen or sulphur atom, or an N-methylimino,N-ethylimino or N-isopropylimino group and

B may represent a methylene, ethylene, n-propylene, n-butylene,α-methyl-ethylene, α-methyl-n-propylene, α-ethyl-n-propylene,α-n-propyl-n-propylene, α,α-dimethyl-n-propylene,α,α-diethyl-n-propylene, β-methyl-n-propylene, -methyl-n-propylene,α-methyl-n-butylene or α,α-dimethyl-n-butylene group, where the positionindices for the alkyl substituents define their position relative to the--CO-- group.

However, the preferred compounds of formula I above are those wherein

R₁ represents a benzyl, thienyl, chlorothienyl, dichlorophenyl,dimethoxyphenyl, tetramethylphenyl or pentamethylphenyl group or aphenyl group optionally substituted by a fluorine or chlorine atom or bya nitro, methyl or trifluoromethyl group,

R₂, R₄ and R₅ each represent a hydrogen atom or a methyl group or

R₂ represents a hydrogen atom or a methyl group and R₄ and R₅ togetherrepresent a carbon-carbon bond,

R₃ represents a pyridyl group,

R₆ represents a hydroxy or methoxy group,

A represents a group of formula ##STR4## wherein R₇ and R₈ eachrepresent a hydrogen atom or together represent a methylene or ethylenegroup and

X represents a sulphur atom or an N-methylimino group, the --CHR₇ --group being linked to the --NR₂ -- group, and

B represents a carbon-carbon bond or a straight-chained C₂₋₄ alkylenegroup,

the enantiomers, the cis and trans isomers where R₄ and R₅ together forma carbon-carbon bond, and the addition salts thereof, particularly forpharmaceutical use the physiologically acceptable salts of addition withorganic or inorganic bases where R₆ represents a hydroxy group.

However, the particularly preferred compounds of formula I are thosewherein

R₁ represents a tetramethylphenyl or pentamethylphenyl group or a phenylgroup substituted in the 4-position by a methyl or trifluoromethyl groupor by a fluorine, chlorine or bromine atom,

R₂, R₄ and R₅ each represent a hydrogen atom or

R₂ represents a hydrogen atom and R₄ and R₅ together represent acarbon-carbon bond,

R₃ represents a 3-pyridyl group,

A represents a group of the formula ##STR5## wherein R₇ and R₈ eachrepresent a hydrogen atom or

R₇ and R₈ together represent a methylene group, and

R₆ represents a hydroxy group,

the enantiomers, the cis and trans isomers thereof where R₄ and R₅together form a carbon-carbon bond, and the physiologically acceptablesalts of addition with organic or inorganic bases.

According to the invention, the new compounds are obtained by thefollowing methods:

a) acylation of a compound of formula ##STR6## (wherein R₂ to R₆, A andB are as hereinbefore defined) with a sulphonic acid derivative offormula

    R.sub.1 --SO.sub.2 X                                       (III)

wherein

R₁ is as hereinbefore defined and

X represents a nucleophilic leaving group such as a halogen atom or analkoxy group, e.g. a chlorine or bromine atom or a methoxy or ethoxygroup.

The reaction is preferably carried out in a solvent such as methanol,ethanol, water/methanol, dioxan, tetrahydrofuran or chloroform,optionally in the presence of an acid binding agent such as potassiumcarbonate, triethylamine or pyridine whilst the latter two may also beused as solvent, expediently at temperatures between 0° and 50° C., butpreferably at ambient temperature.

b) In order to prepare compounds of formula I wherein R₆ represents ahydroxy group:

Cleaving a protecting group from a compound of general formula ##STR7##wherein R₁ to R₅, A and B are as hereinbefore defined and Z represents ahydrolytically, thermolytically or hydrogenolytically removableprotecting group for a carboxy group or a functional derivative of acarboxy group.

Examples of hydrolysable groups include functional derivatives of thecarboxy group such as unsubstituted or substituted amides, esters,thioesters, orthoesters, iminoethers, amidines or anhydrides, thenitrile group, ether groups such as the methoxy, ethoxy, tert.butoxy orbenzyloxy group or lactones and examples of thermolytically removablegroups include for example esters with tertiary alcohols, e.g. thetert.butylester, and examples of hydrogenolytically removable groupsinclude aralkyl groups such as the benzyl group.

The hydrolysis is conveniently carried out either in the presence of anacid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acidor in the presence of a base such as sodium hydroxide or potassiumhydroxide in a suitable solvent such as water, water/methanol, ethanol,water/ethanol, water/isopropanol or water/dioxan at temperatures ofbetween -10° and 120° C., e.g. at temperatures between ambienttemperature and the boiling temperature of the reaction mixture.

If for example a compound of formula IV contains a nitrile oraminocarbonyl group, these groups may be converted to the carboxy group,preferably using 100% phosphoric acid, at temperatures between 100° and180° C., preferably at temperatures between 120° and 160° C., or with anitrite, e.g. sodium nitrite, in the presence of an acid such assulphuric acid, which is conveniently used as solvent at the same time,at temperatures of between 0° and 50° C.

If for example a compound of formula IV contains an acid amide groupsuch as the diethylaminocarbonyl or piperidinocarbonyl group, this groupmay preferably be converted into the carboxy group, preferablyhydrolytically in the presence of an acid such as hydrochloric,sulphuric, phosphoric or trichloroacetic acid or in the presence of abase such as sodium hydroxide or potassium hydroxide in a suitablesolvent such as water, water/methanol, ethanol, water/ethanol,water/isopropanol or water/dioxan at temperatures of between -10° and120° C., e.g. at temperatures between ambient temperature and theboiling temperature of the reaction mixture.

If for example a compound of formula IV contains thetert.butyloxycarbonyl group, the tert.butyl group may also be cleavedthermally, optionally in an inert solvent such as methylene chloride,chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferablyin the presence of a catalytic amount of an acid such asp-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid,preferably at the boiling temperature of the solvent used, e.g. attemperatures of between 40° and 100° C.

If for example a compound of formula IV contains the benzyloxy orbenzyloxycarbonyl group, the benzyl group may also be cleaved byhydrogenolysis in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,methanol/water, ethanol/water, glacial acetic acid, ethyl acetate,dioxan or dimethylformamide, preferably at temperatures of between 0°and 50° C., e.g. at ambient temperature and under a hydrogen pressure of1 to 5 bar. During the hydrogenolysis, a halogen-containing compound cansimultaneously be dehalogenated and any double bond present may behydrogenated.

c) In order to prepare compounds of formula I wherein R₄ and R₅ eachrepresent a hydrogen atom:

Hydrogenation of a compound of formula ##STR8## wherein R₁ to R₃, R₆, Aand B are as hereinbefore defined.

The hydrogenation is carried out in a suitable solvent such as methanol,ethanol, dioxan, ethyl acetate or glacial acetic acid with catalyticallyactivated hydrogen, e.g. with hydrogen in the presence of ahydrogenation catalyst such as Raney nickel, palladium,palladium/charcoal, platinum or platinum/charcoal and under a hydrogenpressure of 1 to 5 bar, or with nascent hydrogen, e.g. in the presenceof iron/hydrochloric acid, zinc/glacial acetic acid,tin(II)chloride/hydrochloric acid or iron(II)sulphate/sulphuric acid, attemperatures of between 0° and 50° C., preferably at ambienttemperature. However, the catalytic hydrogenation may also be carriedout stereoselectively in the presence of a suitable catalyst.

Any nitro group which may be present in the group R₁ may be reduced atthe same time, whilst any chlorine or bromine atom present in the groupR₁ may be replaced by a hydrogen atom.

d) In order to prepare compounds of formula I wherein R₄ and R₅ togetherrepresent a carbon-carbon bond:

Reaction of a compound of formula ##STR9## (wherein R₁ to R₃ and A areas hereinbefore defined) with a compound of formula ##STR10## wherein Band R₆ are defined as hereinbefore,

R₅ ' represents a hydrogen atom or a C₁₋₃ alkyl group and

W represents a triphenylphosphonium halide, dialkylphosphonic acid ormagnesium halide group, and optional subsequent dehydration.

The reaction is preferably carried out in a suitable solvent such asdiethylether, tetrahydrofuran, dioxan or dimethylformamide attemperatures of between -30° and 100° C., preferably at temperatures ofbetween -20° and 25° C.

However, it is particularly advantageous to carry out the reaction witha triphenylphosphonium halide of formula VII in the presence of a basesuch as potassium tert.butoxide or sodium hydride.

During the reaction with a magnesium halide of formula VII, in the caseof the carbinol which is formed primarily in the reaction mixture,should the hydroxy group not be split off then this group is split offin the presence of an acid such as hydrochloric, sulphuric, phosphoricor trichloroacetic acid or in the presence of a base such as sodiumhydroxide or potassium hydroxide in a suitable solvent such as ethanol,isopropanol or dioxan at temperatures of between 0° and 120° C., e.g. attemperatures between ambient temperature and the boiling temperature ofthe reaction mixture.

If according to the invention a compound of formula I is obtainedwherein R₂ represents a hydrogen atom, this can be converted byalkylation into a corresponding compound of formula I wherein R₂represents an alkyl group, or if a compound of formula I is obtainedwherein R₆ represents or contains a hydroxy group, this can be convertedby esterification or amidation into a corresponding compound of formulaI wherein R₆ represents an alkoxy, amino, alkylamino or dialkylaminogroup.

The subsequent alkylation is preferably carried out in a solvent such asmethylene chloride, tetrahydrofuran, dimethylformamide ordimethylsulphoxide in the presence of an alkylating agent such as methyliodide, dimethylsulphate, ethyl bromide, n-propyl bromide or isopropylbromide, optionally in the presence of an acid binding agent such aspotassium carbonate at temperatures of between 0° and 70° C., preferablyat temperatures between 20° and 50° C.

The subsequent esterification or amidation is conveniently carried outin a solvent, e.g. in an excess of the alcohol used, such as methanol,ethanol or isopropanol, or of the amine used such as ammonia,methylamine, n-propylamine or dimethylamine, in the presence of an acidactivating agent such as thionyl chloride or hydrogen chloride gas attemperatures of between 0° and 180° C., but preferably at the boilingtemperature of the reaction mixture.

The compounds of formula I obtained may, furthermore, be resolved intothe enantiomers thereof. Thus, the compounds of formula I obtained whichhave only one optically active centre can be resolved into their opticalantipodes using known methods (see Allinger N. L. and Eliel E. L. in"Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), e.g. byrecrystallisation from an optically active solvent or by reaction withan optically active substance which forms salts with the racemiccompound, particularly bases, and separating the mixture of salts thusobtained, e.g. on the basis of their differing solubilities, into thediastereoisomeric salts from which the free antipodes can be released bythe action of suitable agents. Optically active bases in common useinclude the D- and L-forms of α-phenyl-ethylamine or cinchonidine.

Moreover, the compounds of formula I obtained which have at least 2asymmetric carbon atoms can be resolved into their diastereoisomers onthe basis of their physical-chemical differences using methods known perse, e.g. chromatography and/or fractional crystallisation. A pair ofenantiomers obtained in this way can subsequently be resolved into theoptical antipodes thereof as described above. If for example a compoundof formula I contains two optically active carbon atoms, thecorresponding (R R', S S') and (R S', S R') forms are obtained.

In addition, the compounds of formula I obtained wherein R₄ and R₅together represent a carbon-carbon bond can be converted by conventionalmethods, e.g. by chromatography on a carrier such as silica gel, or bycrystallisation, into their cis and trans isomers.

Furthermore, the new compounds of formula I thus obtained, if theycontain a carboxy group, may if desired subsequently be converted intotheir salts of addition with organic or inorganic bases, and forpharmaceutical in particular use into the physiologically acceptableaddition salts. Examples of such bases include sodium hydroxide,potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

The compounds of formulae II to VII used as starting materials may beobtained by methods known from the literature or else are already knownfrom the literature themselves.

A compound of formula II used as starting material is obtained from acorresponding N-acylamino compound by acylation according toFriedel-Craft, subsequent deacylation and, optionally, subsequentreduction, hydrolysis and/or esterification or by reaction of acorresponding magnesium or lithium compound with a correspondinglysubstituted pyridine compound such as 3-cyano-pyridine,pyridine-3-aldehyde or a pyridine-3-carboxylic acid derivative,optionally followed by oxidation.

The compounds of formulae IV, V and VI used as starting materials areobtained by reacting a corresponding amino compound with a correspondingsulphonyl halide.

The compounds of formula VII used as starting materials are obtained byreacting a corresponding halocarboxylic acid with triphenylphosphine orwith a trialkylphosphonic ester.

As already mentioned hereinbefore, the new compounds and thephysiologically acceptable addition salts thereof with organic orinorganic bases have valuable pharmacological properties, particularlyantithrombotic effect and an inhibitory effect on blood plateletaggregation. They are also thromboxane antagonists and thromboxanesynthesis inhibitors, whilst it is particularly worth noting that thecompounds of formula I have this activity at the same time. They alsohave an effect on PGE₂ production in the lungs and on PGD₂, PGE₂ andPGF₂α production in human thrombocytes.

The following new compounds, for example:

A=6-(2-(4-toluenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoicacid,

B=6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid,

C=6-(2-(4-chlorobenzenesulphonamino)indan-5-yl)-6-(3-pyridyl)hexanoicacid,

D=6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hexanoicacid and

E=6-(4-(2-(4-trifluoromethylbenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

were tested for their biological properties as follows:

1. Antithrombotic activity

Method

The thrombocyte aggregation is measured using the Born and Cross method(J. Physiol. 170: 397 (1964)) in platelet-rich plasma taken from healthyvolunteers. To inhibit coagulation the blood is mixed with 3.14% sodiumcitrate in a ratio by volume of 1:10.

Collagen-induced aggregation

The pattern of the decrease in optical density of the plateletsuspension is photometrically measured and recorded after the additionof aggregation-triggering substance. The rate of aggregation isconcluded from the angle of inclination of the density curve. The pointon the curve where there is maximum light transmittance is used tocalculate the optical density.

The amount of collagen used is as small as possible but sufficient toproduce an irreversible reaction curve. Standard commercial collagenproduced by Hormonchemie of Munich is used. Before the addition of thecollagen the plasma is incubated for 10 minutes with the substance at37° C.

From the measurements obtained an EC₅₀ is determined graphically,indicating a 50% change in the optical density in terms of theinhibition of aggregation.

The Table which follows contains the results found:

    ______________________________________                                        Substance    EC.sub.50  μMol/l!                                            ______________________________________                                        A            0.3                                                              B            0.15                                                             C            0.3                                                              D            1.2                                                              E            0.1                                                              ______________________________________                                    

2. Thromboxane-antagonistic activity

Venous human blood is anti-coagulated with 13 mM Na₃ citrate andcentrifuged for 10 minutes at 170×g. The supernatant platelet-richplasma is passed through a Sepharose 2B column in order to remove theplasma proteins. Aliquots of the platelet suspension obtained areincubated with the test substance, the ligand (³ H-labelled) and amarker (⁴ C-labelled) for 60 minutes at ambient temperature and thencentrifuged for 20 seconds at 10,000×g. The supernatant is removed andthe pellet is dissolved in NaOH. The ³ H activity in the supernatantcorresponds to the free ligand, ¹⁴ C gives the concentration of themarker. ³ H in the pellet corresponds to the bound ligand whilst ¹⁴ C isused to correct for the ligand in the extracellular space. After theprocess has been repeated, the displacement curve is determined from thebinding values for different concentrations of the test substance andthe IC₅₀ is determined.

    ______________________________________                                               Substance                                                                            IC.sub.50  μMol/l!                                           ______________________________________                                               A      0.023                                                                  B      0.02                                                                   C      0.08                                                                   D      0.08                                                                   E      0.028                                                           ______________________________________                                    

3. Determining the inhibitory effect on thromboxane synthetase

Venous human blood is anti-coagulated with 13 mM Na₃ citrate andcentrifuged for 10 minutes at 170×g. The supernatant platelet-richplasma is passed through a Sepharose 2B column in order to remove theplasma proteins. Aliquots of the platelet suspension obtained areincubated with the test substance or with a solvent as control for 10minutes at ambient temperature and after the addition of ¹⁴ C-labelledarachidonic acid incubation is continued for a further 10 minutes. Afterthis has been stopped with 50 μl of citric acid, extraction is carriedout 3× with 500 μl of ethyl acetate and the combined extracts aredistilled off with nitrogen. The residue is taken up in ethyl acetate,placed on TLC film and separated with chloroform:methanol:glacial aceticacid:water (90:8:1:0.8, v/v/v/v). The dried TLC films are placed onX-ray film for 3 days, the autoradiograms were developed and the activezones were marked on the film using the autoradiograms. After cuttingout, the activity is measured in a scintillation counter and theinhibition of the formation of TXB2 is calculated. The IC₅₀ isdetermined by linear interpolation.

    ______________________________________                                               Substance                                                                            IC.sub.50  μMol/l!                                           ______________________________________                                               A      0.003                                                                  B      0.0008                                                                 C      0.003                                                                  D      0.001                                                                  E      0.006                                                           ______________________________________                                    

4. Inhibition of bronchospasm induced by U-46619

Guinea-pigs anaesthetised with ethyl urethane and ventilatedartificially under pressure limitation were repeatedly given intravenousinjections of the thromboxane mimetic U-46619 (= 1R-1α,4α,5β(Z),6α(1E,3S*)!!-7- 6-(3-hydroxy-1-octenyl)-2-oxabicyclo2.2.1!-hept-5-yl!-5-heptenoic acid). The bronchospasms produced wererecorded plethysmographically according to a modification of the methodof Konzett and Rossler (Konzett H. and Rossler R., Arch. exp. Pathol. u.Pharmakol. 195: 71-74 (1940)). The dosage of U-46619 selected (2.5-25μg/kg i.v.) reduces the tidal volume by 60% or more. 10 minutes beforethe thromboxane mimetic is given, increasing doses of the substances tobe tested are injected repeatedly by intraveous route. The percentageinhibition of the reduction in tidal volume is measured by comparison ofthe activity of U-46619 before and after different doses of the testsubstances. The Table which follows contains the ED₅₀ values found,which were determined by graphical extrapolation:

    ______________________________________                                               Substance                                                                            ED.sub.50  μg/μg!                                         ______________________________________                                               A      30                                                                     B      29                                                              ______________________________________                                    

5. Inhibition of the lethal effets of endotoxin

Male Sprague-Dawley rate are primed by intravenous injection with 0.1mg/kg of endotoxin (a lipopolysaccharide from E. coli 0111:B4) one weekbefore the main study. In the main study, a potentially lethal dose ofE. coli (40 mg/kg) is injected intravenously and the subsequentmortality recorded over an observation period of seven days.

The test animals are given test substance B as a suspension in 0.5%tylose by oral route one hour before and 4, 8, 24 and 48 hours after thesecond injection of endotoxin. The following Table contains the valuesfound:

    ______________________________________                                        Amount of Substance B administered                                                                 Rats alive/total                                         at each dosage time point                                                                          after   after                                            (mg/kg)              2 days  7 days                                           ______________________________________                                        0                    2/10    2/10                                             1                    7/10    6/10                                             10                   8/10    5/10                                             ______________________________________                                    

6. Inhibition of bronchospasm induced by arachidonic acid

Guinea-pigs anaesthetised with ethyl urethane and ventilatedartificially under pressure limitation are intravenously injected witharachidonic acid (a thromboxane precursor) and the consequentbronchospasms are recorded using a modified form of the method ofKonzett and Rossler. The doses of arachidonic acid (0.5-2.0 mg/kg) areselected so as to give a 60% reduction in tidal volume. Increasing dosesof test substance B are injected 10 minutes before the arachidonic acid.The percentage inhibition of reduction in tidal volume is determined bycomparison of the maximum reduction after the administration ofarachidonic acid and the corresponding value after pretreatment with thetest substance. The ED₅₀ value for substance B, determined by graphicalextrapolation, was 8.1 μg/kg.

7. Inhibition of antigen-induced anaphylaxis

Male guinea-pigs are sensitised to ovalbumin by the administration of 40mg/kg of ovalbumin, adsorbed onto an aluminium hydroxide adjuvant, byintraperitoneal route. Approximately 6 weeks later they are given asubcutaneous injection of 0.1 mg/kg of mepyramine hydrochloride in orderto reduce the histamine component of the anaphylactic response, which isotherwise very marked in guinea-pigs. 30 minutes later the animals areexposed for 90 seconds to nebulised 0.9% saline solution containing 3%ovalbumin. 10 minutes after the start of inhalation, the animals arekilled by a blow to the neck and the lungs are rapidly removed. Theirvolume, the so-called relaxation volume, is measured. The consequencesof anaphylaxis or bronchoconstriction are associated with an increase inthe relaxation volume (see Drazen I. M. and Austen K. F. in J. Appl.Physiol. 39, 916-919 (1975)).

The following Table contains the values found:

    ______________________________________                                                      Mean lung relaxation volume                                                   (ml)                                                            Animals         First study                                                                             Second study                                        ______________________________________                                        Guinea-pigs exposed to                                                                        7.52      7.51                                                aerosol without test                                                                          (n = 6)   (n = 6)                                             substance                                                                     Guinea-pigs 60 minutes                                                                        4.34      3.81                                                before inhalation pre-                                                                        (n = 6)   (n = 6)                                             treated with 2.5 mg/kg of                                                     substance B by oral route                                                     ______________________________________                                    

Unsensitised animals exposed to the ovalbumin or sensitised animalsexposed to a control aerosol (saline solution) showed a relaxationvolume of 1.5 ml or less in every case.

8. Effect on production of thromboxane and PGE₂ in an isolated lung

Guinea-pigs are killed by a blow to the neck, the lungs are rapidlyremoved and washed with a tyrode solution through the pulmonary artery.The lung is perfused with the same solution (0.5 ml/min.) and ventilatedunder negative pressure (frequency: 52 breaths per minute, maximumpressure -20 cm H₂ O). A 0.1 ml bolus of bradykinin (0.2 μM) is injectedvia the pulmonary arteria on two occasions, with approximately 60minutes between boli. From 30 minutes before the second bradykinininjection 1 μM of substance B is continually added to the lungperfusate. The control lungs are perfused without the added substance.The perfusate is collected for 2 minutes be administration of bradykininand 10 minutes thereafter. The samples are left to stand for 20 minutesat ambient temperature (conversion of thromboxane A₂ into B₂) and arethen frozen at -20° C.

The concentrations of thromboxane B₂ and PGE₂ are determined byradioimmunoassay. The results which follow show that 1 μM of substance Bin the lung perfusate hinders thromboxane production whilst promotingthe formation of PGE₂ :

    ______________________________________                                                                  After 2nd adminis-                                  Substance present                                                                        Ratio of       tration of bradykinin                               in perfusate time                                                                        mediator       After 1st adminis-                                  of 2nd adminis-                                                                          release        tration of bradykinin                               tration of bradykinin                                                                    Thromboxane B.sub.2                                                                          PGE.sub.2                                           ______________________________________                                        1 μM B  0.0     0.0          5.08  2.23                                    control    1.18    0.50   0.84  1.28  1.12 1.09                               ______________________________________                                    

9. Acute toxicity

The acute toxicity of the test substances was determined as a guide ongroups of 10 mice after oral administration of a single dose(observation period: 14 days):

    ______________________________________                                        Substance     Approximate acute toxicity                                      ______________________________________                                        A             250 mg/kg (0 out of 10 animals died)                            B             250 mg/kg (0 out of 10 animals died)                            C             250 mg/kg (0 out of 10 animals died)                            D             250 mg/kg (0 out of 10 animals died)                            E             250 mg/kg (0 out of 10 animals died)                            ______________________________________                                    

In view of their pharmacological properties the new compounds and thephysiologically acceptable addition salts thereof are suitable for thetreatment and prevention of thromboembolic disorders such as coronaryinfarct, cerebral infarct, so-called transient ischaemic attacks,amaurosis fugax and for the prevention of arteriosclerosis andmetastasis and for treating ischaemia, asthma and allergies.

The new compounds and the physiologically acceptable addition saltsthereof are also useful in the treatment of diseases in whichthromboxane-mediated constriction or PGE₂ -mediated dilation of thecapillaries are involved, e.g. in pulmonary hypertension. They may alsobe used to reduce the severity of transplant rejection, to decrease therenal toxicity of substances such as cyclosporin, for the treatment ofkidney diseases, particularly for the treatment or prevention of changesin the kidneys in connection with hypertension, systemic lupus orobstruction of the ureter and in shock states associated withsepticaemia, trauma or burns.

The dose required to achieve such an effect is expediently 0.3 to 4mg/kg of body weight, preferably 0.3 to 2 mg/kg of body weight, two tofour times a day. For this purpose, the compounds of formula I accordingto the invention, optionally combined with other active substances, maybe made into conventional galenic preparations such as tablets, coatedtablets, capsules, powders, suspensions or suppositories, by the use ofone or more inert conventional carriers and/or diluents, e.g. with cornstarch, lactose, glucose, microcrystalline cellulose, magnesiumstearate, polyvinylpyrrolidone, citric acid, tartaric acid, water,water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcelluloseor fatty substances such as hard fat or suitable mixtures thereof.

The present invention also relates to new pharmaceutical compositionscontaining a compound of formula I prepared according to the inventiontogether with a PDE inhibitor or a lysing agent.

Examples of PDE inhibitors include:

2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimido 5,4-d!pyrimidine(dipyridamole),

2,6-bis(diethanolamino)-4-piperidino-pyrimido 5,4-d!pyrimidine(mopidamole),

2-(4-methoxy-phenyl)5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole(pimobendan),

2-(4-hydroxy-phenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole,

1-(1-oxido-thiomorpholino)-3-piperazino-5-methyl-isoquinoline,

6-4-(3,4-dichlorophenylsulphinyl)-butoxy!-3,4-dihydro-2-hydroxy-quinolineand

6- 4-(2-pyridylsulphonyl)-butoxy!-2-hydroxy-quinoline, the oral dailydose being

2.5 to 7.5 mg/kg, preferably 5 mg/kg, for dipyridamole,

15 to 25 mg/kg, preferably 20 mg/kg, for mopidamole,

0.05 to 0.15 mg/kg, preferably 0.08 to 0.10 mg/kg for2-(4-methoxy-phenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole,

0.05 to 0.15 mg/kg, preferably 0.08 to 0.10 mg/kg, for2-(4-hydroxy-phenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole,

0.20 to 2.00 mg/kg, preferably 0.40 to 1.00 mg/kg, for1-(1-oxido-thiomorpholino)-3-piperazino-5-methyl-isoquinoline,

0.10 to 1.00 mg/kg, preferably 0.20 to 0.50 mg/kg, for 6-4-(3,4-dichlorophenylsulphinyl)-butoxy!-3,4-dihydro-2-hydroxy-quinoline,and

0.10 to 1.00 mg/kg, preferably 0.20 to 0.50 mg/kg, for 6-4-(2-pyridylsulphonyl)-butoxy!-2-hydroxy-quinoline,

whilst suitable lysing agents are plasminogen activators such as t-PA,rt-PA, streptokinase, eminase or urokinase, the lysing agent beingadministered by parenteral route, preferably intravenously, e.g. t-PA orrt-PA in a dose of between 15 and 100 mg per patient, urokinase in adose of between 250,000 and 3,000,000 units per patient, eminase in adose of about 30 mg per patient and streptokinase in a dose of between5×10⁴ and 3×10⁷ IU within 5 minutes and 24 hours.

For pharmaceutical use, a new combination containing 1 to 500 mg of aPDE inhibitor, but preferably 2 to 75 mg, plus 10 to 300 mg of acompound of formula I prepared according to the invention, butpreferably 10 to 200 mg thereof, as well as the physiologicallyacceptable addition salts thereof together with one or more inertconventional carriers and/or diluents, e.g. with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, cetyl stearyl alcohol, carboxymethyl cellulose or fattysubstances such as hard fat or suitable mixtures thereof may beformulated to produce conventional galenic preparations such as plain orcoated tablets, capsules, powders, suspensions or suppositories. Inorder to achieve the desired results the preparation will beadministered to adults 2 to 4 times a day, but preferably 3 to 4 times aday.

Furthermore, for pharmaceutical use, a new combination containing alysing agent in the dosages given hereinbefore plus 10 to 300 mg of acompound of formula I prepared according to the invention, preferably 10to 200 mg thereof, and the physiologically acceptable addition saltsthereof may be incorporated in the usual parenteral, preferably theusual intravenous, preparations such as ampoules or infusions, and thepreparation can be administered within 5 minutes and 24 hours.

Naturally, the individual active substances in the above-mentionedcombinations may be administered if desired.

The Examples which follow are intended to illustrate the invention. Insuch examples, all "parts" are by weight and the eluant ratios are byvolume.

EXAMPLE 16-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

a) 2-(p-Chlorobenzenesulphonylamino)ethyl-benzene

To a mixture of 150 ml of ethylene chloride and 150 ml of water areadded 30.3 g of 2-phenylethylamine, 12 g of sodium hydroxide and 0.5 gof tetrabutylammonium bromide. 65.5 g of 4-chlorobenzenesulphonic acidchloride are added to the mixture in batches with stirring. After 30minutes the organic phase is separated off, evaporated down and theresidue is recrystallised from toluene.

Yield: 65 g (88% of theory),

Melting point: 90° C.

b) 4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl-3-pyridyl ketone

100 g of aluminium trichloride are slowly combined with 25.5 ml ofdimethylformamide in such a way that the temperature does not exceed 70°C. To this mixture are added 35.6 g of nicotinic acid chloridehydrochloride and 49 g of 2-(4-chlorobenzenesulphonylamino)ethyl benzeneand it is heated to 100° C. for 2 hours. The reaction mixture is pouredonto ice, neutralised and extracted with ethylene chloride. The organicphase is evaporated down and the residue is chromatographed over asilica gel column using ethylene chloride/ethanol (40:1).

Yield: 16.7 g (25% of theory),

Melting point: 150°-152° C. C₂₀ H₁₇ ClN₂ O₃ S (400.91)

    ______________________________________                                        Calculated: C     59.92    H   4.28   N   6.99                                Found:            60.06        3.98       6.87                                ______________________________________                                    

c)6-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

To a suspension of 6.7 g of 4-carboxybutyltriphenylphosphonium bromideand 4.5 g of potassium tert.butoxide in 100 ml of tetrahydrofuran areadded 4.0 g of4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl-3-pyridyl ketone at 0°C. and the mixture is stirred for 2 hours. The reaction mixture isdecomposed with ice water and washed with toluene. The aqueous phase isacidified and extracted with ethylene chloride. The organic extract isconcentrated by evaporation and the residue is chromatographed over asilica gel column with ethylene chloride/ethanol (20:1). The fractionwhich contains the product is evaporated down, the residue is dissolvedin ethyl acetate and the cyclohexylammonium salt is precipitated by theaddition of 2 ml of cyclohexylamine.

Yield: 1.9 g (36% of theory),

Melting point: 95° C. (decomp.) C₂₅ H₂₅ ClN₂ O₄ S×1/2 cyclohexylamine(534.61)

    ______________________________________                                        Calculated: C     62.91    H   5.94   N   6.55                                Found:            62.80        6.03       6.72                                ______________________________________                                    

EXAMPLE 26-(1-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)naphthyl))-6-(3-pyridyl)hex-5-enoicacid

a) 1-(2-(p-Chlorobenzenesulphonylamino)ethyl)naphthalene

Prepared from 1-(2-aminoethyl)naphthalene and 4-chlorobenzenesulphonicacid chloride analogously to Example 1a. The crude product was purifiedby column chromatography on silica gel using ethylenechloride/cyclohexane (2:1).

Yield: 92% of theory,

Melting point: 98°-99° C. C₁₈ H₁₆ ClNO₂ S (345.87)

    ______________________________________                                        Calculated: C     62.51    H   4.66   N   4.05                                Found:            62.39        4.68       3.86                                ______________________________________                                    

b) 4-(2-(4-Chlorobenzenesulphonylamino)ethyl)naphthyl-3-pyridyl ketone

Prepared from nicotinic acid chloride hydrochloride and1-(2-(p-chlorobenzenesulphonylamino)ethyl)naphthalene analogously toExample 1b. The crude product was purified by column chromatography onsilica gel using ethylene chloride/ethyl acetate (5:1).

Yield: 22% of theory,

Resin, R_(f) value: 0.41 (silica gel: ethylene chloride/ethylacetate=3:1) C₂₄ H₁₉ ClN₂ S (450.96)

    ______________________________________                                        Calculated: C     63.92    H   4.25   N   6.21                                Found:            63.54        4.43       6.01                                ______________________________________                                    

c)6-(1-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)naphthyl))-6-(3-pyridyl)hex-5-enoicacid

Prepared from4-(2-(4-chlorobenzenesulphonylamino)ethyl)-naphthyl-3-pyridyl ketone and4-carboxybutyltriphenylphosphonium bromide analogously to Example 1c butwithout precipitation of a salt using cyclohexylamine.

Yield: 43% of theory,

Resin, R_(f) value: 0.52 (silica gel: ethylene chloride/ethylacetate=4:1) C₂₉ H₂₇ ClN₂ O₄ S (535.09)

    ______________________________________                                        Calculated: C     65.10    H   5.09   N   5.24                                Found:            64.91        5.35       5.20                                ______________________________________                                    

EXAMPLE 36-(5-(2-(4-Fluorobenzenesulphonylamino)ethyl)-N-methyl-pyrrol-2-yl)-6-(3-pyridyl)hex-5-enoicacid

a)5-(2-(4-Fluorobenzenesulphonylamino)ethyl)-N-methyl-pyrrol-2-yl-3-pyridylketone

A solution of 14.1 g of2-(2-(4-fluorobenzenesulphonylamino)-ethyl)-N-methyl-pyrrole in 100 mlof toluene and 50 ml of dimethylformamide is combined with 9.8 g ofnicotinic acid chloride hydrochloride, added in batches. The mixture isrefluxed for 2 hours, poured onto ice, neutralised and extracted withethylene chloride. The crude product is chromatographed over a silicagel column with ethylene chloride/ethanol (20:1).

Yield: 4.6 g (24% of theory),

Melting point: 140° C. C₁₉ H₁₈ FN₃ O₃ S (387.44)

    ______________________________________                                        Calculated: C     58.90    H   4.68   N   10.85                               Found:            58.62        4.52       10.70                               ______________________________________                                    

b) 6-(5-(2-(4-Fluorobenzenesulphonylamino)ethyl)-N-methyl-pyrrol-2-yl)-6-(3-pyridyl)hex-5-enoic acid

Prepared from5-(2-(4-fluorobenzenesulphonylamino)ethyl)-N-methyl-pyrrol-2-yl-3-pyridylketone and 4-carboxybutyltriphenylphosphonium bromide analogously toExample 1c, but the crude product is purified by recrystallisation fromwater/isopropanol.

Yield: 55% of theory,

Melting point: 190° C. C₂₄ H₂₆ FN₃ O₄ S (471.56)

    ______________________________________                                        Calculated: C     61.13    H   5.56   N   8.91                                Found:            61.23        5.72       9.00                                ______________________________________                                    

EXAMPLE 46-(5-(2-(4-Chlorobenzenesulphonylamino)ethyl)thiophen-2-yl)-6-(3-pyridyl)hex-5-enoicacid

a) 2-(2-(p-Chlorobenzenesulphonylamino)ethyl)thiophene

Prepared from 2-(2-aminoethyl)-thiophene and 4-chlorobenzenesulphonicacid chloride analogously to Example 1a.

Yield: 69% of theory,

Melting point: 93° C. C₁₂ H₁₂ ClNO₂ S₂ (301.83)

    ______________________________________                                        Calculated: C     47.75    H   4.01   N   4.64                                Found:            47.75        3.88       4.45                                ______________________________________                                    

b) 5-(2-(4-Chlorobenzenesulphonylamino)ethyl)thiophen-2-yl-3-pyridylketone

A solution of 15 g of2-(2-(4-chlorobenzenesulphonylamino)ethyl)-thiophene in 50 ml ofethylene chloride is added dropwise to a suspension of 20 g of aluminiumtrichloride and nicotinic acid chloride hydrochloride in 150 ml ofethylene chloride. The mixture is heated for 11/2 hours to 50° C., thenpoured onto ice, the precipitate is suction filtered and recrystallisedfrom methanol.

Yield: 3.7 g (17% of theory),

Melting point: 154°-160° C. C₁₈ H₁₅ ClN₂ O₃ S×1/2 HCl (433.06)

    ______________________________________                                        Calculated: C     49.92    H   3.58   N   6.47                                Found:            50.29        3.82       6.38                                ______________________________________                                    

c)6-(5-(2-(4-Chlorobenzenesulphonylamino)ethyl)thiophen-2-yl)-6-(3-pyridyl)hex-5-enoicacid

Prepared from5-(2-(4-chlorobenzenesulphonylamino)ethyl)thiophen-2-yl-3-pyridyl ketoneand 4-carboxybutyltriphenylphosphonium bromide analogously to Example1c, but after column chromatography the product is recrystallised fromethyl acetate.

Yield: 20% of theory,

Melting point: 138° C. C²³ H₂₃ ClN₂ O₄ S (491.04)

    ______________________________________                                        Calculated: C     56.26    H   4.72   N   5.71                                Found:            56.24        4.67       5.70                                ______________________________________                                    

EXAMPLE 5

6-(2-(4-Chlorobenzenesulphonylamino)tetralin-6- and7-yl)-6-(3-pyridyl)hex-5-enoic acid

a) 2-Acetylaminotetralin-6- and 7-yl-3-pyridyl ketone

Prepared from 2-acetylaminotetralin and nicotinic acid chlorideanalogously to Example 1b.

Yield: 35% of theory,

Resin, R_(f) value: 0.28 (silica gel: ethylene chloride/ethanol=10:1)C₁₈ H₁₈ N₂ O₂ (294.40)

    ______________________________________                                        Calculated: C     73.45    H   6.16   N   9.52                                Found:            73.38        6.23       9.26                                ______________________________________                                    

b) 2-(4-Chlorobenzenesulphonylamino)tetralin-6- and 7-yl-3-pyridylketone

The mixture of 2-acetylaminotetralin-6- and 7-yl-3-pyridyl ketone isrefluxed for 20 hours in 150 ml of concentrated hydrochloric acid. Thesolvent is removed and the residue is treated with4-chlorobenzenesulphonic acid chloride according to Example 1a.

Yield: 35% of theory,

Melting point: 152°-155° C. (ethyl acetate) C₂₂ H₁₉ ClO₃ S (426.94)

    ______________________________________                                        Calculated: C     61.89    H   4.49   N   6.56                                Found:            61.92        4.45       6.46                                ______________________________________                                    

c) 6-(2-(4-Chlorobenzenesulphonylamino)tetralin-6- and7-yl)-6-(3-pyridyl)hex-5-enoic acid

Prepared from the mixture of2-(4-chlorobenzenesulphonylamino)tetralin-6- and 7-yl-3-pyridyl ketoneand 4-carboxybutyltriphenyl-phosphonium bromide analogously to Example1c, but with no precipitation of a salt using cyclohexylamine.

Yield: 93% of theory,

Resin, R_(f) value: 0.30 (silica gel: ethylene chloride/ethanol=10:1)C₂₇ H₂₇ ClN₂ O₄ S (511.07)

    ______________________________________                                        Calculated: C     63.46    H   5.33   N   5.48                                Found:            63.29        5.31       5.22                                ______________________________________                                    

EXAMPLE 66-(5-(2-(4-Fluorobenzenesulphonylamino)ethyl)-N-methyl-pyrrol-2-yl)-6-(3-pyridyl)hexanoicacid

A mixture of 2.36 g of6-(5-(2-(4-fluorobenzenesulphonylamino)ethyl)-N-methyl-pyrrol-2-yl)-6-(3-pyridyl)hex-5-enoicacid, 0.4 g of sodium hydroxide and 1 g of 10% palladium/charcoal in 50ml of methanol is hydrogenated under 5 bar of hydrogen pressure. Thenthe catalyst is filtered off, the filtrate is evaporated down, theresidue is diluted with water, acidified and extracted with ethylenechloride. The organic extract is evaporated down and the residuerecrystallised from ethyl acetate.

Yield: 2 g (85% of theory),

Melting point: 146°-149° C.

    ______________________________________                                        Calculated: C     60.88    H   5.96   N   8.87                                Found:            61.11        6.02       8.93                                ______________________________________                                    

EXAMPLE 76-(2-(4-Toluenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoic acid

a)-2-Acetylaminoindan-5-yl-3-pyridyl ketone

At 70° C., 42.7 g of nicotinic acid chloride hydrochloride are added inbatches to 150 g of aluminium chloride and 31 ml of dimethylformamide.35 g of 2-acetylaminoindane are added in batches to this mixture. Afterthe mixture has been further heated at 80° C. it is cooled after 2 hoursand the mixture is poured onto 200 g of ice and 100 ml of concentratedhydrochloric acid. The acidic solution is carefully neutralised withsodium hydroxide solution and then extracted 4× with 250 ml ofchloroform. The organic phases are collected, dried over sodium sulphateand concentrated by rotary evaporation.

Yield: 43 g (76% of theory),

Melting point: 165°-167° C. C₁₇ H₁₆ N₂ O₂ (280.32)

    ______________________________________                                        Calculated: C     72.84    H   5.75   N   9.99                                Found:            72.70        5.72       9.75                                ______________________________________                                    

b) 2-Aminoindan-5-yl-3-pyridyl ketone

51 g of 2-acetylamino-indan-5-yl-3-pyridyl ketone are refluxed for 16hours with 250 ml of half concentrated hydrochloric acid. The solutionis concentrated and then adjusted to pH 12 using 15N sodium hydroxidesolution. The precipitate formed is washed with water and recrystallisedfrom 100 ml of isopropanol.

Yield: 42 g (97% of theory),

Melting point: 205° C. (decomp.) C₁₅ H₁₄ N₂ O (238.29)

    ______________________________________                                        Calculated: C     75.61    H   5.92   N   11.75                               Found:            75.44        6.04       11.85                               ______________________________________                                    

c) 2-(4-Toluenesulphonylamino)indan-5-yl-3-pyridyl ketone

21 g of 2-aminoindan-5-yl-3-pyridyl ketone are dissolved together with18.9 g of p-toluenesulphonic acid chloride in 250 ml of methylenechloride. Then 9.2 g of triethylamine are added dropwise. After 4 hoursthe suspension is rotary-evaporated to dryness. The residue is suspendedin water, made alkaline with sodium hydroxide solution and then suctionfiltered.

Yield: 30.4 g (88% of theory),

Melting point: 225°-228° C. C₂₂ H₂₀ N₂ O₃ S (392.47)

    ______________________________________                                        Calculated: C     67.33    H   5.14   N   7.14                                Found:            67.12        5.16       6.95                                ______________________________________                                    

d) 6-(2-(4-Toluenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoicacid

5 g of 2-(4-toluenesulphonylamino)indan-5-yl-3-pyridyl ketone are addedto a suspension of 8 g of 4-carboxybutyl-triphenylphosphonium bromideand 5.6 g of potassium tert.butoxide in 100 ml of tetrahydrofuran undera nitrogen atmosphere. The suspension is stirred for a further 2 hoursat 0° C., then added to water and washed with toluene. Then the aqueousphase is acidified with 3N formic acid and the precipitate formed istaken up in methylene chloride. The organic phase is dried overmagnesium sulphate and rotary-evaporated. The oil obtained ischromatographed over a silica gel column using ethyl acetate as eluant.

Yield: 3.4 g (56% of theory),

Melting point: 150°-156° C. C₂₇ H₂₈ N₂ O₄ S (476.59)

    ______________________________________                                        Calculated: C     68.04    H   5.92   N   5.88                                Found:            67.90        6.10       5.82                                ______________________________________                                    

EXAMPLE 8 Methyl6-(2-(4-bromobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoate

a) 6-(2-Acetylamino-indan-5-yl)-6-(3-pyridyl)hex-5-ene carboxylic acid

11.1 g of 4-carboxybutyltriphenylphosphonium bromide and 8.0 g ofpotassium tert.butoxide are placed in 100 ml of absolute tetrahydrofuranand stirred at 10° C. under a nitrogen atmosphere. Then 5.6 g of2-acetylaminoindan-5-yl-3-pyridyl ketone are added in batches andstirred at ambient temperature for 2 hours. The reaction mixture is thenpoured onto ice water and washed with toluene. The aqueous phase isadjusted to pH 5 using 3N hydrochloric acid. The precipitate formed istaken up in methylene chloride, washed with water, dried over sodiumsulphate and rotary evaporated. The product mixture is chromatographedover a silica gel column using ethyl acetate:ethanol:glacial acetic acid(94:5:1) as eluant.

Yield: 7.2 g (99% of theory),

Oil, R_(f) value: 0.20 (silica gel: ethyl acetate/ethanol/glacial aceticacid=94:5:1)

b) Methyl 6-(2-aminoindan-5-yl)-6-(3-pyridyl)hex-5-enoate

3.1 g of 6-(2-acetylaminoindan-5-yl)-6-(3-pyridyl)hex-5-enoic acid arerefluxed for 15 hours with 20 ml of half concentrated hydrochloric acidand then rotary evaporated. The residue is then added to 50 ml ofmethanol saturated with dry hydrogen chloride. After 30 minutes stirringat ambient temperature the reaction mixture is rotary evaporated todryness. The residue is taken up in 1N sodium hydroxide solution andadjusted to pH 10. It is then extracted 3 times with 50 ml of methylenechloride, the organic phase is dried and rotary evaporated.

Yield: 2.45 g (50% of theory)

Resin, R_(f) =0.50 (silica gel: toluene/dioxan/methanol/ammonia=2:5:2:1)C₂₁ H₂₄ N₂ O₂ (336.44)

    ______________________________________                                        Calculated: C     74.97    H   7.19   N   8.33                                Found:            75.00        7.01       8.11                                ______________________________________                                    

c) Methyl 6-(2-(4-bromobenzenesulphonylamino)indan-5-yl)-6-3-pyridylhex-5-enoate

3.4 g of methyl 6-(2-aminoindan-5-yl)-6-(3-pyridyl)hex-5-enoate isplaced in 40 ml of chloroform together with 3.3 g of4-bromobenzenesulphonic acid chloride and 1.8 g of triethylamine areadded in batches at ambient temperature. After 30 minutes the solutionis washed with water, dried and rotary evaporated. The yellow oil isthen chromatographed over a silica gel column using cyclohexane/ethylacetate (1:2).

Yield: 4.5 g (81% of theory),

Resin, R_(f) value: 0.25 (silica gel: cyclohexane/ethyl acetate=1:1) C₂₇H₂₇ BrN₂ O₄ S (555.48)

    ______________________________________                                        Calculated: C     58.38    H   4.90   N   5.04                                Found:            58.30        5.16       4.94                                ______________________________________                                    

The following compounds are obtained analogously:

methyl6-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoate

Resin, R_(f) value: 0.32 (silica gel: cyclohexane/ethyl acetate=1:1) C₂₇H₂₇ ClN₂ O₄ S (511.03)

    ______________________________________                                        Calculated: C     63.46    H   5.32   N   5.42                                Found:            63.58        5.49       5.35                                ______________________________________                                    

methyl6-(2-(4-fluorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoate

Resin, R_(f) value: 0.82 (silica gel:toluene/dioxan/methanol/ammonia=2:5:2:1) C₂₇ H₂₇ FN₂ O₄ S (494.58)

    ______________________________________                                        Calculated: C     65.57    H   5.50   N   5.66                                Found:            65.39        5.78       5.48                                ______________________________________                                    

methyl6-(2-(2-thiophenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoate

Resin, R_(f) value: 0.25 (silica gel: cyclohexane/ethyl acetate=1:1) C₂₅H₂₆ N₂ O₄ S₂ (482.61)

    ______________________________________                                        Calculated: C     62.22    H   5.43   N   5.80                                Found:            62.28        5.60       5.53                                ______________________________________                                    

methyl6-(2-(2,5-dichlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoate

Resin, R_(f) value: 0.38 (silica gel: cyclohexane/ethyl acetate=1:1) C₂₇H₂₆ Cl₂ N₂ O₄ S (545.48)

    ______________________________________                                        Calculated: C     59.45    H   4.80   N   5.14                                Found:            59.41        5.02       4.96                                ______________________________________                                    

methyl6-(2-(4-nitrobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoate

Resin, R_(f) value: 0.38 (silica gel: cyclohexane/ethyl acetate=1:1) C₂₇H₂₇ N₃ O₆ S (521.59)

    ______________________________________                                        Calculated: C     62.17    H   5.22   N   8.06                                Found:            62.22        5.45       7.90                                ______________________________________                                    

methyl 6-(2-(benzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoate

Resin, R_(f) value: 0.20 (silica gel: cyclohexane/ethyl acetate=1:1) C₂₇H₂₈ N₂ O₄ S (476.59)

    ______________________________________                                        Calculated: C     68.04    H   5.92   N   5.88                                Found:            67.98        6.07       5.60                                ______________________________________                                    

EXAMPLE 96-(2-(4-Bromobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoicacid

3.7 g of methyl6-(2-(4-bromobenzenesulphonylamino)-indan-5-yl)-6-(3-pyridyl)hex-5-enoateare refluxed for 15 minutes in 30 ml of ethanol and with 1N of 15Nsodium hydroxide solution. After cooling the solution is rotaryevaporated and the residue is taken up in water and washed with 30 ml ofmethylene chloride. Then the aqueous phase is adjusted to pH 4 usinghydrochloric acid. The precipitate formed is washed and dried.

Yield: 3.2 g (88% of theory),

Melting point: 83°-102° C. C₂₅ H₂₆ BrN₂ O₄ S (541.46)

    ______________________________________                                        Calculated: C     57.68    H   4.65   N   5.17                                Found:            57.58        4.64       4.99                                ______________________________________                                    

The following compounds are obtained analogously:

6-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoicacid

Melting point: 83°-98° C. C₂₆ H₂₅ ClN₂ O₄ S (497.01)

    ______________________________________                                        Calculated: C     62.83    H   5.07   N   5.64                                Found:            62.64        5.02       5.57                                ______________________________________                                    

6-(2-(4-fluorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoicacid

Melting point: 73°-90° C. C₂₆ H₂₅ FN₂ O₄ S (480.55)

    ______________________________________                                        Calculated: C     64.98    H   5.24   N   5.83                                Found:            64.85        5.23       5.76                                ______________________________________                                    

6-(2-(2-thiophenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoicacid

Melting point: 67°-90° C. C₂₄ H₂₄ N₂ O₄ S₂ (468.58)

    ______________________________________                                        Calculated: C     61.52    H   5.16   N   5.98                                Found:            61.38        5.04       5.70                                ______________________________________                                    

6-(2-benzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoic acid

Melting point: 70°-97° C. C₂₆ H₂₆ N₂ O₄ S (462.58)

    ______________________________________                                        Calculated: C     67.51    H   5.67   N   6.06                                Found:            67.44        5.87       6.18                                ______________________________________                                    

6-(2-(4-nitrobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)-hex-5-enoicacid

Melting point: 73°-92° C. C₂₆ H₂₅ N₃ O₆ S (507.56)

    ______________________________________                                        Calculated: C     61.53    H   4.96   N   8.28                                Found:            61.45        5.06       8.18                                ______________________________________                                    

6-(2-(2,5-dichlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoicacid

Melting point: 79°-100° C. C₂₆ H₂₄ Cl₂ N₂ O₄ S (531.45)

    ______________________________________                                        Calculated: C     58.76    H   4.55   N   5.27                                Found:            58.78        4.65       5.11                                ______________________________________                                    

EXAMPLE 106-(4-(2-(4-Chlorobenzenesulphonylaminoethyl)phenyl-6-(3-pyridyl)-hexanoicacid

a) 4-(2-Acetylaminoethyl)phenyl-3-pyridyl ketone

180 g of aluminium chloride are mixed with 35 ml of dimethylformamideand the temperature rises to 70° C. Then 66.8 g of nicotinic acidchloride hydrochloride are added, followed by 49 g of2-acetylaminoethylbenzene at 70° C. After 2 hours the mixture is cooledand 60 ml of ethylene chloride are added. Then the mixture is pouredonto ice water and 180 ml of concentrated hydrochloric acid. The aqueousphase is made alkaline with sodium hydroxide solution and then extractedwith 3 times 100 ml of ethylene chloride. The organic phase is dried androtary evaporated.

Yield: 70.4 g (87% of theory),

Oil, R_(f) value: 0.47 (silica gel: ethylene chloride/methanol=9:1) C₁₆H₁₆ N₂ O₂ (268.32)

    ______________________________________                                        Calculated: C     71.62    H   6.01   N   10.44                               Found:            71.82        6.20       10.30                               ______________________________________                                    

b) 6-(4-(2-Acetylaminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoic acid

Prepared analogously to Example 7d from4-(2-acetylaminoethyl)-phenyl-3-pyridyl ketone and4-carboxybutyl-triphenylphosphonium bromide.

Yield: 57% of theory,

Melting point: 80°-85° C. C₂₁ H₂₄ N₂ O₃ (352.4)

    ______________________________________                                        Calculated: C     71.57    H   6.86   N   7.95                                Found:            71.23        7.06       7.94                                ______________________________________                                    

The following compounds are obtained analogously:

5-(4-(2-acetylaminoethyl)phenyl)-5-(3-pyridyl)pent-4-enoic acid

Yield: 87% of theory,

Resin, R_(f) value: 0.35 (silica gel: chloroform/methanol=10:1) C₂₀ H₂₂N₂ O₃ (338.4)

    ______________________________________                                        Calculated: C     70.98    H   6.55   N   8.28                                Found:            70.79        6.39       7.88                                ______________________________________                                    

7-(4-(2-acetylaminoethyl)phenyl)-7-(3-pyridyl)hept-6-enoic acid

Yield: 49% of theory,

Resin, R_(f) value: 0.37 (silica gel: chloroform/methanol=10:1) C₂₂ H₂₆N₂ O₃ (366.5)

    ______________________________________                                        Calculated: C     72.11    H   7.15   N   7.64                                Found:            71.82        7.41       7.58                                ______________________________________                                    

c) 6-(4-(2-Acetylaminoethyl)phenyl-6-(3-pyridyl)hexanoic acid

7.05 g of 6-(4-(2-acetylaminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoic acidare dissolved in 85 ml of 0.7N sodium hydroxide solution andcatalytically reduced at 40° C. with 1 g of palladium/charcoal. Afterthe catalyst has been removed by suction filtering the residue isacidified to pH 6 and the oil precipitated is taken up in ethyl acetateand evaporated down. The crude product is recrystallised from methanol.

Yield: 4.7 g (66% of theory),

Melting point: 135°-139° C. C₂₁ H₂₆ N₂ O₂ (354.5)

    ______________________________________                                        Calculated: C     71.16    H   7.39   N   7.90                                Found:            70.85        7.50       7.85                                ______________________________________                                    

The following compounds are obtained analogously:

5-(4-(2-acetylaminoethyl)phenyl)-5-(3-pyridyl)pentanoic acid

Yield: 58% of theory,

Resin, R_(f) value: 0.37 (silica gel: chloroform/methanol=10:1) C₂₀ H₂₄N₂ O₃ (340.4)

    ______________________________________                                        Calculated: C     70.56    H   7.11   N   8.23                                Found:            70.40        6.97       7.94                                ______________________________________                                    

7-(4-(2-acetylaminoethyl)phenyl)-7-(3-pyridyl)heptanoic acid

Yield: 98% of theory,

Resin, R_(f) value: 0.43 (silica gel: chloroform/methanol=10:1) C₂₂ H₂₈N₂ O₃ (368.5)

    ______________________________________                                        Calculated: C     71.71    H   7.66   N   7.60                                Found:            71.58        7.77       7.22                                ______________________________________                                    

d) 6-(4-(2-Aminoethyl)phenyl)-6-(3-pyridyl)hexanoic acid

4.0 g of 6-(4-(2-acetylaminoethyl)phenyl)-6-(3-pyridyl)hexanoic acid arerefluxed for 18 hours with 50 ml of half concentrated hydrochloric acid.The mixture is then rotary evaporated and the residue is purified bychromatography over a column of silica gel using methanol.

Yield: 2.3 g (66% of theory),

Resin, R_(f) value: 0.27 (silica gel: methanol) C₁₉ H₂₄ N₂ O₂ (312.4)

    ______________________________________                                        Calculated: C     73.05    H   7.74   N   8.97                                Found:            72.81        7.63       8.83                                ______________________________________                                    

The following compounds are obtained analogously:

5-(4-(2-aminoethyl)phenyl)-5-(3-pyridyl)pentanoic acid

Yield: 96% of theory,

Resin, R_(f) value: 0.33 (silica gel: methanol) C₁₈ H₂₂ N₂ O₂ ×0.5 HCl(317.1)

    ______________________________________                                        Calculated: C     68.17    H   7.43   N   9.39                                Found:            68.27        7.31       8.99                                ______________________________________                                    

7-(4-(2-aminoethyl)phenyl)-7-(3-pyridyl)heptanoic acid

Yield: 96% of theory,

Resin, R_(f) value: 0.59 (silica gel: methanol) C₂₀ H₂₆ N₂ O₂ (326.4)

    ______________________________________                                        Calculated: C     73.59    H   8.03   N   8.58                                Found:            73.48        8.00       8.37                                ______________________________________                                    

e)6-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hexanoicacid

1.9 g of 6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hexanoic acid aresuspended in 150 ml of dioxan and 20 ml of 5% potassium carbonatesolution are added thereto. 1.54 g of 4-chlorobenzenesulphonic acidchloride in 20 ml of dioxan are added to this mixture at ambienttemperature. After 5 hours it is rotary evaporated to dryness, theresidue is taken up in a little sodium hydroxide solution and thenprecipitated with dilute acetic acid. The precipitate is collected,dried and then chromatographed over a silica gel column usingchloroform/methanol (10:1) as eluant.

Yield: 1.8 g (61% of theory),

Resin, R_(f) value: 0.48 (silica gel: chloroform/methanol=10:1) C₂₅ H₂₇ClN₂ O₄ S (487.03)

    ______________________________________                                        Calculated: C     61.65    H   5.59   N   5.79                                Found:            61.59        5.40       5.74                                ______________________________________                                    

The following compounds are obtained analogously:

6-(4-(2-(4-fluorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hexanoicacid

Yield: 11% of theory,

Resin, R_(f) value: 0.53 (silica gel: chloroform/methanol=10:1) C₂₅ H₂₇FN₂ O₄ S (470.60)

    ______________________________________                                        Calculated: C     63.81    H   5.78   N   5.95                                Found:            63.75        5.92       5.80                                ______________________________________                                    

6-(4-(2-(4-toluenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hexanoicacid

Yield: 13% of theory,

Resin, R_(f) value: 0.55 (silica gel: chloroform/methanol=10:1) C₂₆ H₂₉N₂ O₄ S (4 66.60)

    ______________________________________                                        Calculated: C     66.93    H   6.48   N   6.00                                Found:            66.81        6.57       5.94                                ______________________________________                                    

6-(4-(2-(4-bromobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hexanoicacid

Yield: 24% of theory,

Resin, R_(f) value: 0.34 (silica gel: chloroform/methanol=20:1) C₂₅ H₂₇BrN₂ O₄ S (531.50)

    ______________________________________                                        Calculated: C     56.50    H   5.12   N   5.27                                Found:            56.41        5.31       5.17                                ______________________________________                                    

EXAMPLE 115-(4-(2-(4-Fluorobenzenesulphonylamino)ethyl)phenyl)-5-(3-pyridyl)pentanoicacid

Prepared analogously to Example 10e from5-(4-(2-aminoethyl)phenyl)-5-(3-pyridyl)pentanoic acid and4-fluorobenzenesulphonic acid chloride.

Yield: 28% of theory,

Resin, R_(f) value: 0.33 (silica gel: chloroform/methanol=10:1) C₂₄ H₂₅FN₂ O₄ S (456.50)

    ______________________________________                                        Calculated: C     63.14    H   5.52   N   6.94                                Found:            63.04        5.60       5.96                                ______________________________________                                    

EXAMPLE 125-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-5-(3-pyridyl)pentanoicacid

Prepared analogously to Example 10e from5-(4-(2-aminoethyl)phenyl)-5-(3-pyridyl)pentanoic acid and4-chlorobenzenesulphonic acid chloride.

Yield: 21% of theory,

Melting point: 70° C. C₂₄ H₂₅ ClN₂ O₄ S (473.00)

    ______________________________________                                        Calculated: C     60.94    H   5.33   N   5.92                                Found:            61.01        5.35       5.70                                ______________________________________                                    

EXAMPLE 137-(4-(2-(4-Toluenebenzenesulphonylamino)ethyl)phenyl)-7-(3-pyridyl)heptanoicacid

Prepared analogously to Example 10e from7-(4-(2-aminoethyl)phenyl)-7-(3-pyridyl)heptanoic acid and4-toluenesulphonic acid chloride.

Yield: 78% of theory,

Resin, R_(f) value: 0.42 (silica gel: chloroform/methanol=10:1) C₂₇ H₃₂N₂ O₄ S (480.60)

    ______________________________________                                        Calculated: C     67.47    H   6.71   N   5.83                                Found:            67.34        6.71       5.74                                ______________________________________                                    

EXAMPLE 147-(4-(2-(4-Fluorobenzenesulphonylamino)ethyl)phenyl)-7-(3-pyridyl)heptanoicacid

Prepared analogously to Example 13 from7-(4-(2-aminoethyl)phenyl)-7-(3-pyridyl)heptanoic acid and4-fluorobenzenesulphonic acid chloride.

Yield: 66% of theory,

Resin, R_(f) value: 0.20 (silica gel: chloroform/methanol=10:1) C₂₆ H₂₉FN₂ O₄ S (484.6)

    ______________________________________                                        Calculated: C     64.44    H   6.03   N   5.72                                Found:            64.48        5.99       5.72                                ______________________________________                                    

EXAMPLE 15 Methyl5-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-5-(3-pyridyl)pentanoate

2.0 g of5-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-5-(3-pyridyl)pentanoicacid are dissolved in 30 ml of methanol and mixed with 3 ml of thionylchloride at 0° C. The solution is stirred overnight, then rotaryevaporated and the residue is chromatographed over a silica gel column.

Yield: 1.1 g (53% of theory),

Resin, R_(f) value: 0.65 (silica gel: chloroform/methanol=95:5) C₂₆ H₂₉ClN₂ O₄ S (501.1)

    ______________________________________                                        Calculated: C     62.33    H   5.83   N   5.59                                Found:            62.36        6.01       5.42                                ______________________________________                                    

EXAMPLE 16 Methyl5-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)-pent-4-enoat

3.7 g of5-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)pent-4-enoicacid are dissolved in 30 ml of methanol into which dry hydrogen chlorideis introduced. The solution is stirred overnight and then rotaryevaporated. Whilst cooling with ice, the base is liberated with aqueouspotassium carbonate solution and then extracted with methylene chloride.The solution is rotary evaporated and the residue is chromatographedover a silica gel column.

Yield: 2.5 g (52% of theory),

Resin, R_(f) value: 0.53 (silica gel: toluene/dioxan/ethanol/aceticacid=9:1:1:0.6) C₂₆ H₂₅ ClN₂ O₄ S (497.01)

    ______________________________________                                        Calculated: C     62.80    H   5.10   N   5.60                                Found:            62.67        5.39       5.40                                ______________________________________                                    

The following compound is obtained analogously:

Methyl7-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-7-(3-pyridyl)hept-6-enoate

Yield: 73% of theory,

Resin, R_(f) value: 0.31 (silica gel: cyclohexane/ethyl acetate=1:1) C₂₈H₂₉ ClN₂ O₄ S (525.06)

    ______________________________________                                        Calculated: C     64.05    H   5.56   N   5.33                                Found:            64.45        6.15       5.05                                ______________________________________                                    

EXAMPLE 175-(2-(4-Chlorobenzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)pent-4-enoicacid

Prepared from methyl5-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)pent-4-enoateby hydrolysis with sodium hydroxide solution.

Yield: 95% of theory,

Melting point: 94°-114° C. C₂₅ H₂₃ ClN₂ O₄ S (482.98)

    ______________________________________                                        Calculated: C     62.20    H   4.80   N   5.80                                Found:            62.14        4.70       5.81                                ______________________________________                                    

The following compound is obtained analogously:

7-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-7-(3-pyridyl)hept-6-enoicacid

Yield: 94% of theory,

Melting point: 66°-90° C. C₂₇ H₂₇ ClN₂ O₄ S (511.03)

    ______________________________________                                        Calculated: C     63.50    H   5.30   N   5.50                                Found:            63.65        5.29       5.30                                ______________________________________                                    

EXAMPLE 18 (Z)- and(E)-6-(2-(4-Chlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoicacid

1.9 g of methyl6-(2-(4-chlorobenzenesulphonylamino)-indan-5-yl)-6-(3-pyridyl)hex-5-enoateis chromatographed over a silica gel column using the eluant ethylenechloride/ethyl acetate/glacial acetic acid (70:30:5). The faster runningsubstance is the Z isomer. The (Z) and (E) esters thus obtained arehydrolysed with sodium hydroxide solution according to Example 17.

(Z)-6-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)-hex-5-enoicacid

Yield: 200 mg (10% of theory),

Melting point: 70°-100° C. C₂₆ H₂₅ ClN₂ O₄ S (497.01)

    ______________________________________                                        Calculated: C     62.83    H   5.07   N   5.64                                Found:            62.72        5.24       5.47                                ______________________________________                                    

(E)-6-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)-hex-5-enoicacid

Yield: 400 mg (20% of theory),

Melting point: 75°-103° C. C₂₆ H₂₅ ClN₂ O₄ S (497.01)

    ______________________________________                                        Calculated: C     62.83    H   5.07   N   5.64                                Found:            62.75        5.14       5.43                                ______________________________________                                    

EXAMPLE 196-(2-(4-Chlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hexanoicacid

3.0 g of6-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoicacid are dissolved in 50 ml of 0.3N sodium hydroxide solution andhydrogenated with 1 g of palladium/charcoal at 40° C. and 3.5 bar for 12hours. The catalyst is then removed by suction filtering and thefiltrate is adjusted to pH 4 to 5. The product precipitated is separatedoff and taken up in chloroform. The organic extract is washed withwater, dried and evaporated down. Then the mixture is chromatographedover a silica gel column using the eluant ethylene chloride/ethylacetate/glacial acetic acid (70:30:2). The third fraction contains thedesired product.

Yield: 0.4 g (13% of theory),

Melting point: 85°-100° C. C₂₆ H₂₇ ClN₂ O₄ S

    ______________________________________                                        Calculated: C     62.58    H   5.45   N   5.61                                Found:            62.54        5.45       5.79                                ______________________________________                                    

EXAMPLE 207-(2-(4-Chlorobenzenesulphonylamino)indan-5-yl)-7-(3-pyridyl)heptanoicacid

Prepared analogously to Example 19 by reduction of7-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-7-(3-pyridyl)hept-6-enoicacid with platinum/charcoal.

Yield: 40% of theory,

Resin, R_(f) value: 0.3 (silica gel: ethylene chloride/ethylacetate/acetic acid=10:3:0.5) C₂₆ H₂₉ ClN₂ O₄ S (501.03)

    ______________________________________                                        Calculated: C     62.32    H   5.83   N   5.59                                Found:            62.56        6.00       5.32                                ______________________________________                                    

EXAMPLE 215-(2-(Benzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)pentanoic acid

Prepared from5-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)pent-4-enoicacid analogously to Example 19 by catalytic hydrogenation in thepresence of platinum as catalyst.

Yield: 37% of theory,

Melting point: 80°-110° C. C₂₅ H_(ClN) ₂ O₄ S (485.00)

    ______________________________________                                        Calculated: C     61.91    H   5.19   N   5.77                                Found:            61.85        5.33       6.05                                ______________________________________                                    

EXAMPLE 227-(2-(Benzenesulphonylamino)indan-5-yl)-7-(3-pyridyl)heptanoic acid

Prepared from7-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-7-(3-pyridyl)hept-6-enoicacid by catalytic hydrogenation analogously to Example 21.

Yield: 10% of theory,

Melting point: 60°-75° C. C₂₇ H₂₉ ClN₂ O₄ S (513.05)

    ______________________________________                                        Calculated: C     63.21    H   5.69   N   5.46                                Found:            63.43        5.88       5.63                                ______________________________________                                    

EXAMPLE 233-(2-(4-Toluenesulphonylamino)indan-5-yl)-3-(3-pyridyl)-prop-2-enoicacid

a) Ethyl3-(2-(4-toluenesulphonylamino)indan-5-yl)-3-(3-pyridyl)prop-2-enoate

At 5° C., 9.84 g of triethylphosphonoacetate are added to a suspensionof 9.6 g of potassium tert.butoxide in 100 ml of tetrahydrofuran and 25ml of dimethylformamide. After 30 minutes stirring at 0° C., 15.5 g of2-(4-toluenesulphonylamino)indan-5-yl-3-pyridyl ketone are added. Themixture is then refluxed for 5 hours. The solution is poured onto icewater and extracted 4 times with 50 ml of methylene chloride. It is thendried, rotary evaporated and the residue is chromatographed over asilica gel column using ethylene chloride/ethyl acetate 9:1 as eluant.

Yield: 17.2 g (93% of theory),

R_(f) value: 0.46/0.35 (silica gel: ethylene chloride/ethyl acetate=1:1)

b) 3-(2-(4-Toluenesulphonylamino)indan-5-yl)-3-(3-pyridyl)-prop-2-enoicacid

4.2 g of ethyl3-(2-(4-toluenesulphonylamino)indan-5-yl)-3-(3-pyridyl)-prop-2-enoateare refluxed for 30 minutes in 40 ml of ethanol and 1.5 ml of 15N sodiumhydroxide solution. Then the cooled solution is washed 3 times with 50ml of methylene chloride and then acidified. The precipitate formed iswashed, dried and then recrystallised from n-butanol.

Yield: 2.3 g (58% of theory),

Melting point: 228°-230° C. C₂₃ H₂₂ N₂ O₄ S (422.5)

    ______________________________________                                        Calculated: C     65.38    H   5.24   N   6.63                                Found:            65.32        5.17       6.48                                ______________________________________                                    

EXAMPLE 244-(2-(4-Toluenesulphonylamino)indan-5-yl)-3-(3-pyridyl)propanoic acid

Prepared analogously to Example 19 from3-(2-(4-toluenesulphonylamino)indan-5-yl)-3-(3-pyridyl)prop-2-enoate andsubsequent precipitation from dioxan by the addition ofdiisopropylether.

Yield: 74% of theory,

Melting point: 85°-97° C. C₂₃ H₂₂ N₂ O₄ S×0.8 dioxan (424.51)

    ______________________________________                                        Calculated: C     63.57    H   6.19   N   5.66                                Found:            63.39        6.30       5.62                                ______________________________________                                    

EXAMPLE 256-(4-(2-(4-Fluorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)-hex-5-enoicacid

3.1 g of 6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoic acid(prepared analogously to Example 10d) are stirred into 150 ml of dioxanwith 5 ml of saturated potassium carbonate solution. Then 2.9 g of4-fluorobenzenesulphonic acid chloride in 20 ml of dioxan are added andthe resulting mixture is stirred overnight at ambient temperature.Acetic acid is added and a precipitate is formed. This is separated offand taken up in ethyl acetate, then dried and evaporated down. Finally,the residue is chromatographed over a silica gel column usingchloroform/methanol 20:1 as eluant.

Yield: 0.5 g (10% of theory),

Resin, R_(f) value: 0.55 (silica gel: chloroform/methanol=10:1) C₂₅ H₂₅FN₂ O₄ S (470.6)

    ______________________________________                                        Calculated: C     64.09    H   5.38   N   5.98                                Found:            63.77        5.59       6.00                                ______________________________________                                    

The following compounds are obtained analogously:

6-(4-(2-(4-toluenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

Yield: 13% of theory,

Resin, R_(f) value: 0.5 (silica gel: chloroform/methanol=10:1) C₂₆ H₂₈ ₂O₄ S (464.6)

    ______________________________________                                        Calculated: C     67.22    H   6.07   N   6.03                                Found:            67.06        6.21       5.86                                ______________________________________                                    

6-(4-(2-(4-bromobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)-hex-5-enoicacid

Yield: 20% of theory,

Resin, R_(f) value: 0.4 (silica gel: chloroform/methanol=10:1) C₂₅ H₂₅BrN₂ O₄ S (529.5)

    ______________________________________                                        Calculated: C     56.71    H   4.76   N   5.29                                Found:            56.72        4.58       5.12                                ______________________________________                                    

EXAMPLE 267-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-7-(3-pyridyl)-hept-6-enoicacid

Prepared from 4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl-3-pyridylketone analogously to Example 7d.

Yield: 83% of theory,

Resin, R_(f) value: 0.5 (silica gel: ethylene chloride/methanol=5:1) C₂₆H₂₇ ClN₂ O₄ S (499.02)

    ______________________________________                                        Calculated: C     62.58    H   5.45   N   5.62                                Found:            62.48        5.40       5.62                                ______________________________________                                    

EXAMPLE 276-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)-hex-5-enoicacid diethylamide

1.0 g of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid are dissolved in 15 ml of tetrahydrofuran and stirred for 15minutes with 0.49 g of carbonyldiimidazole. Then 1 ml of diethylamine isadded and the mixture is refluxed for 2 hours. It is then concentratedby evaporation and the residue is taken up in ethyl acetate and dried.Finally, it is chromatographed over a silica gel column using ethylacetate as eluant.

Yield: 0.6 g (54% of theory),

Oil, R_(f) value: 0.23 (silica gel: ethyl acetate) C₂₉ H₃₄ ClN₃ O₃ S(540.12)

    ______________________________________                                        Calculated: C     64.48    H   6.34   N   7.78                                Found:            64.42        6.60       7.52                                ______________________________________                                    

The following compound is obtained analogously:

6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid benzylamide

Yield: 51% of theory,

Resin, R_(f) value: 0.37 (silica gel: ethyl acetate) C₃₂ H₃₂ ClN₃ O₃ S(574.14)

    ______________________________________                                        Calculated: C     66.94    H   5.61   N   7.31                                Found:            66.72        5.44       7.10                                ______________________________________                                    

EXAMPLE 286-(4-(2-(N-Methyl-4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

2.0 g of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)-phenyl)-6-(3-pyridyl)hex-5-enoicacid are stirred overnight in 10 ml of 4N sodium hydroxide solution, 100ml of methylene chloride, 80 mg of benzyl trimethylammonium chloride and0.85 g of methyl iodide. Then the organic phase is separated off and theaqueous phase is acidified to pH 5. The product precipitated isseparated off and taken up in methylene chloride, dried and evaporateddown. Finally, the residue is chromatographed with ethylenechloride/methanol (97:3) over a silica gel column.

Yield: 0.43 g (21% of theory),

Melting point: 121°-125° C. C₂₆ H₂₇ ClN₂ O₄ S (499.02)

    ______________________________________                                        Calculated: C     62.58    H   5.45   N   5.61                                Found:            62.53        5.54       5.53                                ______________________________________                                    

EXAMPLE 296-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)-2,2-dimethyl-hex-5-enoicacid

a)6-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)-2,2-dimethyl-hex-5-enoicacid piperidide

Prepared analogously to Example 7d from 4-triphenylphosphonium butanoicacid piperidide bromide and4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl-3-pyridyl ketone.

Yield: 6.7% of theory,

Resin, R_(f) value: 0.4 (silica gel: ethyl acetate) C₃₂ H₃₈ ClN₃ O₃ S(580.16)

    ______________________________________                                        Calculated: C     66.24    H   6.60   N   7.24                                Found:            66.15        6.33       7.11                                ______________________________________                                    

b)6-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)-2,2-dimethyl-hex-5-enoicacid

0.35 g of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)-2,2-dimethyl-hex-5-enoicacid piperidide are refluxed for 8 hours in 20 ml of 6N hydrochloricacid. Then the mixture is evaporated down and the residue is dissolvedin sodium hydroxide solution and adjusted to pH 4 using hydrochloricacid. The precipitate formed is suction filtered and chromatographedover a silica gel column using ethylene chloride/methanol (10:1).

Yield: 0.12 g (39% of theory),

Resin, R_(f) value: 0.5 (silica gel: ethylene chloride/methanol=9:1) C₂₇H₂₉ ClN₂ O₄ S (513.04)

    ______________________________________                                        Calculated: C     63.21    H   5.70   N   5.46                                Found:            63.08        5.58       5.60                                ______________________________________                                    

EXAMPLE 306-(4-(2-(2,4,6-Trimethylbenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

a) Methyl 6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoate

Prepared by hydrolysis of6-(4-(2-acetylaminoethyl)-phenyl)-6-(3-pyridyl)hex-5-enoic acid andsubsequent esterification with methanol analogously to Example 8b.

Yield: 87% of theory,

Resin, R_(f) value: 0.6 (silica gel:dioxan/toluene/methanol/ammonia=5:2:2:1) C₂₀ H₂₄ N₂ O₂ (324.42)

    ______________________________________                                        Calculated: C     74.05    H   7.46   N   8.63                                Found:            73.85        7.58       8.52                                ______________________________________                                    

b)6-(4-(2-(2,4,6-Trimethylbenzenesulphonylamino)ethyl)phenyl)6-(3-pyridyl)hex-5-enoicacid

A mixture of 3.24 g of methyl6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoate, 2.2 g of2,4,6-trimethylbenzenesulphonic acid chloride and 100 ml oftriethylamine in 50 ml of dichloromethane is stirred for 30 minutes atambient temperature. Then the reaction mixture is washed twice withwater, dried and evaporated down. The residue is purified over a silicagel column using ethyl acetate. The crude product obtain is heated in amixture of 32 ml of ethanol and 5 ml of 4N sodium hydroxide solution for30 minutes to 50° to 60° C. The reaction mixture is evaporated down, theresidue is taken up in 50 ml of water and washed with ethyl acetate. Theaqueous phase is adjusted to pH 5 by the addition of citric acid andextracted twice with ethyl acetate. The organic phase is dried,evaporated down and the residue is chromatographed over a silica gelcolumn using ethyl acetate. The crude product is then recrystallisedfrom ethyl acetate/diisopropyl ether.

Yield: 1.35 g (28% of theory),

Melting point: 79°-83° C. C₂₈ H₃₂ N₂ O₄ S (492.64)

    ______________________________________                                        Calculated: C     68.27    H   6.55   N   5.68                                Found:            68.00        6.51       5.68                                ______________________________________                                    

The following compounds are obtained analogously:

6-(4-(2-(2,3,5,6-tetramethylbenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

Melting point: 135°-136° C. C₂₉ H₃₄ N₂ O₄ S (506.67)

    ______________________________________                                        Calculated: C     68.75    H   6.76   N   5.33                                Found:            68.91        6.81       5.37                                ______________________________________                                    

6-(4-(2-(2,3,4,5,6-pentamethylbenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

Melting point: 158°-160° C. (ethyl acetate/diethyl ether) C₃₀ H₃₆ N₂ O₄S (520.69)

    ______________________________________                                        Calculated: C     69.20    H   6.97   N   5.38                                Found:            69.00        7.14       5.49                                ______________________________________                                    

6-(4-(2-(4-methoxybenzenesulphonylamino)ethyl)phenyl)6-(3-pyridyl)hex-5-enoicacid

Melting point: 104°-106° C. C₂₆ H₂₈ N₂ O₅ S (480.58)

    ______________________________________                                        Calculated: C     64.98    H   5.87   N   5.83                                Found:            64.90        6.02       5.99                                ______________________________________                                    

6-(4-(2-(3,4-dimethoxybenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

Yield: 18% of theory,

Resin, R_(f) value: 0.36 (silica gel: dichloromethane/ethylacetate=6:4+3% acetic acid) C₂₇ H₃₀ N₂ O₆ S (510.61)

    ______________________________________                                        Calculated: C     63.51    H   5.92   N   5.49                                Found:            63.21        5.79       5.33                                ______________________________________                                    

6-(4-(2-(4-trifluoromethylbenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

Melting point: 140°-143° C. (ethyl acetate/petroleum ether) C₂₆ H₂₅ F₃N₂ O₄ S (518.56)

    ______________________________________                                        Calculated: C     60.22    H   4.86   N   5.40                                Found:            60.05        4.77       5.66                                ______________________________________                                    

6-(4-(2-(5-chlorothiophene-2-sulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

Melting point: 113°-115° C. C₂₃ H₂₃ ClN₂ O₄ S₂ (491.03)

    ______________________________________                                        Calculated: C     56.26    H   4.72   N   5.70                                Found:            55.96        4.70       5.79                                ______________________________________                                    

6-(4-(2-(phenylmethanesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid C₂₆ H₂₈ N₂ O₄ S (464.58)

Resin, R_(f) value: 0.64 (silica gel: ethyl acetate)

    ______________________________________                                        Calculated: C     67.22    H   6.07   N   6.03                                Found:            67.27        6.22       5.88                                ______________________________________                                    

EXAMPLE 31 E- andZ-6-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

a) 4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl-3-pyridyl ketone

156 g of 4-(2-acetylaminoethyl)phenyl-3-pyridyl ketone are heated for 16hours in 800 ml of 6N hydrochloric acid. The solution is evaporated downand the residue is taken up in a mixture of 200 ml of water and 500 mlof dioxan. By the addition of 10N sodium hydroxide solution a pH of 8 to10 is established. Then a solution of 126 g of 4-chlorobenzenesulphonicacid chloride in 150 ml of dioxan and 10N sodium hydroxide solution isadded dropwise at ambient temperature so as to maintain a pH of 8 to 10.The reaction mixture is added to a mixture of 1 kg of ice and 400 ml oftoluene and the precipitate is suction filtered. The crude productprecipitated is recrystallised from toluene.

Yield: 148 g (65% of theory),

Melting point: 159°-160° C. C₂₀ H₁₇ ClN₂ O₃ S (400.91)

    ______________________________________                                        Calculated: C     59.92    H   4.28   N   6.99                                Found:            60.00        4.10       6.91                                ______________________________________                                    

b)E-6-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

222 g of 4-carboxybutyl-triphenylphosphonium bromide are suspended in2000 ml of tetrahydrofuran and cooled to -20° C. To this suspension areadded 156 g of potassium tert.butoxide followed by 155 g of4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-3-pyridyl ketone. Themixture is stirred for 1.5 hours whilst the temperature is allowed torise to 10° C. The reaction mixture is poured onto 5000 ml of ice water.The aqueous phase is washed with ethyl acetate and then adjusted to pH 5by the addition of citric acid. The precipitate is suction filtered andrecrystallised from water/ethanol.

Yield: 140 g (75% of theory),

Melting point: 159°-160° C. C₂₅ H₂₅ ClN₂ O₄ S (485.00)

    ______________________________________                                        Calculated: C     61.91    H   5.20   N   5.78                                Found:            61.67        5.06       5.70                                ______________________________________                                    

c)Z-6-(4-(2-(4-Chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

The mother liquor from Example 31b is evaporated down and extracted withethyl acetate. The organic extract is evaporated down and the residue ischromatographed over a silica gel column with (ethylene chloride/ethylacetate=6:4+3% acetic acid). The faster running fraction is collected,evaporated down and the residue is recrystallised from ethylacetate/diethyl ether.

Yield: 7.8 g (3% of theory),

Melting point: 94°-95° C. C₂₅ H₂₅ ClN₂ O₄ S (485.00)

    ______________________________________                                        Calculated: C     61.91    H   5.20   N   5.78                                Found:            61.66        5.23       5.87                                ______________________________________                                    

EXAMPLE 326-(2-(4-Chlorobenzenesulfonylamino)-1,2,3,4-tetrahydronaphth-6-yl)-6-(3-pyridyl)hex-5-enoicacid

a) 2-Amino-6-bromo-1,2,3,4-tetrahydronaphthaline hydrochloride

55.8 g of titanium tetrachloride were dropped cautiously to 700 ml ofethylene glycol dimethylether at 0° C. Subsequently 22.3 g of sodiumboron hydride and then a solution of 33.5 g of6-bromo-2-oximino-1,2,3,4-tetrahydronaphthaline were added to thereaction mixture. After stirring for four hours, the mixture was pouredon ice, made alkaline with concentrated ammonia and filtrated overkieselguhr. The filtrate was extracted with methylene chloride andevaporated in vacuum. The obtained residue was dissolved in ether andthe hydrochloride was precipitated by addition of isopropanolichydrochloric acid.

Yield: 20,2 g (55% of theory),

Melting point: 237° C. C₁₀ H₁₂ BrN×HCl (262,5)

    ______________________________________                                        Calculated: C     45,74    H   4,99   N   5,33                                Found:            45,90        5,22       5,24                                ______________________________________                                    

b) 2-tert.Butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydronaphthaline

44 ml of 1N sodium hydroxide and subsequently 4,8 g of di-tert.butyldicarbonate were added to a solution of 5.25 g of2-amino-6-bromo-1,2,3,4-tetrahydronaphthaline in 75 ml of dioxane/water(2:1) at 0° C. After stirring for 12 hours at room temperature, themixture was evaporated, mixed with water and extracted with ethylacetate. The organic phase was evaporated and the residue obtainedrecrystallised from petroleum ether.

Yield: 5,2 g (80% of theory),

Melting point: 111° C. C₁₅ H₂₀ BrNO₂ (326,23)

    ______________________________________                                        Calculated: C     55,23    H   6,18   N   4,29                                Found:            55,08        6,29       4,51                                ______________________________________                                    

c)2-tert.Butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydronaphth-6-yl-3-pyridylmethanol8.8 ml of a solution of n-butyl lithium in hexane (2.5 mol) was droppedto a solution of 3.25 g of2-tert.butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydro-naphthaline in 50ml of absolute tetrahydrofurane cooled to -70° C. and stirring wascontinued for 1.5 hours at -50° C. Subsequently, 1.1 g ofpyridine-3-aldehyde were dropped into the mixture at -70° C. Afterstirring for one hour, the reaction mixture was poured on ice andextracted with ethyl acetate. The organic phase was washed with water,dried and evaporated. The obtained residue was recrystallised fromcyclohexane/ethyl acetate.

Yield: 1,85 g (52% of theory),

Melting point: 135° C. C₂₁ H₂₆ N₂ O₃ (354,45)

    ______________________________________                                        Calculated: C     71,16    H   7,39   N   7,90                                Found:            70,96        7,46       7,86                                ______________________________________                                    

d)2-(4-Chlorobenzenesulfonylamino)-1,2,3,4-tetrahydronapth-6-yl-3-pyridylketone

1,75 g of2-tert.butoxycarbonylamino-1,2,3,4-tetrahydronaphth-6-yl-3-pyridylmethanol were stirred in 30 ml of chloroform with 17,5 g of manganesedioxide for one hour at room temperature. After filtering thesuspension, the filtrate was evaporated and the obtained residue wasstirred in 10 ml of 2N hydrochloric acid for one hour at 40°-50° C. Thereaction mixture was made alkaline by addition of concentrated ammoniaand extracted with ethyl acetate. The organic phase was washed withwater and evaporated. 0.86 g of 4-chlorobenzenesulphonic acid chlorideand additionally 1 g of triethylamine were added to a solution of theobtained residue in 20 ml of methylene chloride at 0° C. After stirringfor two hours, the reaction mixture was poured on ice and extracted withmethylene chloride. The organic phase was washed with water, dried andevaporated. The obtained residue was recrystallised from ethylacetate/petroleum ether.

Yield: 1,2 g (57% of theory),

Melting point: 170°-172° C. C₂₂ H₁₉ ClN₂ O₃ S (426,92)

    ______________________________________                                        Calculated: C     61,89    H   4,49   N   6,56                                Found:            61,63        4,62       6,39                                ______________________________________                                    

e)6-(2-(4-Chlorobenzenesulfonylamino)-1,2,3,4-tetrahydronaphth-6-yl)-6-(3-pyridyl)hex-5-enoicacid

Prepared from2-(4-chlorobenzenesulfonylamino)-l,2,3,4-tetrahydronaphth-6-yl-3-pyridylketone and 4-carboxybutyl-triphenylphosphonium bromide analogously toExample 31b.

Yield: 63% of theory,

Melting point: 172° C. C₂₇ H₂₇ ClN₂ O₄ S

    ______________________________________                                        Calculated: C     63,46    H   5,33   N   5,48                                Found:            63,42        5,41       5,43                                ______________________________________                                    

EXAMPLE I

Tablets containing 100 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-3-enoicacid

    ______________________________________                                        Composition:                                                                  1 tablet contains:                                                            ______________________________________                                        Active substance       100.0  mg                                              Lactose                80.0   mg                                              Corn starch            34.0   mg                                              Polyvinylpyrrolidone   4.0    mg                                              Magnesium stearate     2.0    mg                                                                     220.0  mg                                              ______________________________________                                    

Preparation process:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist masses have been screened (2.0 mmmesh size) and dried in a rack dryer at 50° C. they are screened again(1.5 mm mesh) and the lubricant is added. The mixture produced is formedinto tablets.

Weight of tablet: 220 mg

Diameter: 9 mm, biplanar, facetted on both sides and notched on oneside.

EXAMPLE II

Hard gelatin capsules containing 150 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-3-enoicacid

    ______________________________________                                        1 capsule contains:                                                           ______________________________________                                        Active substance     150.0     mg                                             Dried corn starch about                                                                            180.0     mg                                             Dried lactose about  87.0      mg                                             Magnesium stearate   3.0       mg                                                                  about 320.0                                                                             mg                                             ______________________________________                                    

Preparation:

The active substance is mixed with the excipients, passed through a 0.75mm mesh screen and homogeneously mixed in a suitable apparatus. Thefinal mixture is packed into size 1 hard gelatin capsules.

Capsule contents: about 320 mg

Capsule shell: size 1 hard gelatin capsule.

EXAMPLE III

Suppositories containing 150 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-3-enoicacid

    ______________________________________                                        1 suppository contains:                                                       ______________________________________                                        Active substance        150.0   mg                                            Polyethyleneglycol (M.W. 1500)                                                                        550.0   mg                                            Polyethyleneglycol (M.W. 6000)                                                                        460.0   mg                                            Polyoxy polyoxy ethylene sorbitan                                                                     840.0   mg                                            monostearate                                                                                          2000.0  mg                                            ______________________________________                                    

Preparation:

After the suppository masses have been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

EXAMPLE IV

Suspensions containing 50 mg of6-(4-(2-(4-chlorobenzene-sulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-3-enoicacid

    ______________________________________                                        100 ml of suspension contain:                                                 ______________________________________                                        Active substance         1.0    g                                             Sodium salt of carboxymethylcellulose                                                                  0.2    g                                             Methyl p-hydroxybenzoate 0.05   g                                             Propyl p-hydroxybenzoate 0.01   g                                             Glycerol                 5.0    g                                             70% Sorbitol solution    50.0   g                                             Flavouring               0.3    g                                             Distilled water ad       100    ml                                            ______________________________________                                    

Preparation:

Distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the addition of thesorbitol solution and flavouring, the suspension is evacuated toeliminate air, with stirring.

5 ml of suspension contain 50 mg of active substance.

EXAMPLE V

Tablets containing 150 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

    ______________________________________                                        Composition:                                                                  1 tablet contains:                                                            ______________________________________                                        Active substance       150.0  mg                                              Powdered lactose       89.0   mg                                              Corn starch            40.0   mg                                              Colloidal silica       10.0   mg                                              Polyvinylpyrrolidone   10.0   mg                                              Magnesium stearate     1.0    mg                                                                     300.0  mg                                              ______________________________________                                    

Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a 1.5 mm mesh screen. The granules dried at 45° C. are rubbedthrough the same screen again and mixed with the specified amount ofmagnesium stearate. Tablets are compressed from the mixture.

Weight of tablet: 300 mg

Punch: 10 mm, flat

EXAMPLE VI

Film-coated tablets containing 75 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid

    ______________________________________                                        1 tablet core contains:                                                       ______________________________________                                        Active substance        75.0   mg                                             Calcium phosphate       93.0   mg                                             Corn starch             35.5   mg                                             Polyvinylpyrrolidone    10.0   mg                                             Hydroxypropylmethylcellulose                                                                          15.0   mg                                             Magnesium stearate      1.5    mg                                                                     230.0  mg                                             ______________________________________                                    

Preparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Using a tablet making machine,compressed tablets are produced about 13 mm in diameter which are thenrubbed through a 1.5 mm mesh screen on a suitable machine and mixed withthe remaining magnesium stearate. These granules are compressed in atablet making machine to form tablets of the desired shape.

Weight of core: 230 mg

Punch: 9 mm, convex

The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose. The finished film coatedtablets are glazed with beeswax.

Weight of film coated tablet: 245 mg

Obviously all the other compounds of general formula I may be used asactive substances in the galenic preparations described above.

EXAMPLE VII

Film coated tablets containing 75 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)-hex-5-enoicacid (Substance B)+75 mg of PDE inhibitor

    ______________________________________                                        A powder mixture of                                                           ______________________________________                                        Dipyridamole      25%                                                         Substance B       25%                                                         Fumaric acid      15%                                                         Cellulose         20%                                                         Corn starch        8%                                                         Polyvinylpyrrolidone                                                                             6%                                                         ______________________________________                                    

is moistened with water in a mixing apparatus and granulated through ascreen with a mesh size of 1.5 mm. After drying and screening again, 1%magnesium stearate is added and 10 mm biconvex tablets are producedweighing 300 mg. These tablets are sprayed withhydroxypropylmethylcellulose lacquer until they weigh 312 mg.

EXAMPLE VIII

Hard gelatin capsules containing 200 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid (Substance B)+50 mg of PDE inhibitor

10 kg of dipyridamole, 20 kg of fumaric acid, 11.5 kg ofpolyvinylpyrrolidone, 40 kg of substance B, 1.5 kg of silicon dioxideand 0.8 kg of magnesium stearate are mixed for 15 minutes in a cubemixer. This mixture is fed into a roller compactor followed by a drygranulating apparatus with screening device. The fraction from 0.25 to1.0 mm is used. The capsule filling machine is set so that each size 0capsule contains the quantity of granules corresponding to 50 mg of PDEinhibitor and 200 mg of substance B.

EXAMPLE IX

Hard gelatin capsules containing 100 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid (Substance B)+250 mg of PDE inhibitor

a) Granules

125 kg of mopidamole, 50 kg of fumaric acid and 13.5 kg of lactose aremixed together and moistened with a solution of water/polyethyleneglycol6000. After granulation through a screen with a mesh size of 1.0 mm anddrying at 45° C., 1.4 kg of stearic acid are added.

b) Coated tablet

100 kg of substance B, 7.5 kg of hydroxypropylmethylcellulose, 2.5 kg ofsilicon dioxide and 15 kg of carboxymethylcellulose are moistened withethanol and granulated through a screen with a mesh size of 1.5 mm.After drying, 1 kg of magnesium stearate is added and the granules arecompressed to form biconvex tablets weighing 126 mg and having adiameter of 5.5 mm.

These cores are coated in several steps with a coating suspensionconsisting of 5.6 kg of saccharose, 0.5 kg of gum arabic and 3.8 kg oftalc until the tablets weight 135 mg.

c) Filling

In a special capsule making machine, hard gelatin capsules of size 0long are packed with a quantity of granules corresponding to 250 mg ofPDE inhibitor and the coated tablet containing 100 mg of substance B isplaced on top.

EXAMPLE X

Suspension containing 10 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid (Substance B)+100 mg of dipyridamole per 5 g.

The suspension has the following composition:

    ______________________________________                                        (1) Dipyridamole     2.0%                                                     (2) Substance B      0.2%                                                     (3) Sorbitol         20.8%                                                    (4) Cellulose        7.5%                                                     (5) Sodium carboxymethylcellulose                                                                  2.5%                                                     (6) Flavour correctors/preservatives                                                               1.8%                                                     (7) Water            65.2%                                                    ______________________________________                                    

Ingredients (3) to (6) are stirred into hot water under high shearforces. After cooling, ingredients (1), (2) and (7) are incorporated inthe viscous suspension.

EXAMPLE XI

Delayed release form containing 50 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid (Substance B)+200 mg of dipyridamole

a) Pellet I

    ______________________________________                                        A mixture of                                                                  ______________________________________                                        Substance B              50.0   kg                                            Lysine                   12.5   kg                                            High polymeric hydroxypropylcellulose                                                                  52.5   kg                                            Triacetin                4.0    kg                                            Ethylcellulose           2.5    kg                                            Magnesium stearate       3.5    kg                                            ______________________________________                                    

is kneaded with ethanol in a special extruder and extruded in the formof spaghetti (diameter 1 mm) which is formed into pellets in aspheronizer. These pellets are then thoroughly dried.

b) Pellet II

300 kg of tartaric acid starter pellets are sprayed, in a specialcontainer, with a suspension of isopropanol, dipyridamole andpolyvinylpyrrolidone until the active substance pellets produced containabout 45% of dipyridamole.

These pellets are sprayed with a lacquer consisting of methacrylicacid/methylmethacrylate copolymer (sold under the name Eudragit S) andhydroxymethylcellulose phthalate (sold under the name HP 55) in a weightratio of 85:15 to 50:50. The organic lacquer solution also containplasticiser and talc. Two pellet components are sprayed with 5 and 7% ofcoating composition and different ratios of lacquer components withinthe limits specified. The two components are mixed together to give thefollowing in vitro release:

Conditions (corresponding to USPXXI, Basket method, 100 rpm,

1st hour in artificial gastric juice, pH 1.2, 2nd to 6th hours inartificial intestinal juice (phosphate buffer), pH 5.5):

Release of active substance per hour:

    ______________________________________                                               1st hour                                                                             about 30%                                                              2nd hour                                                                             about 25%                                                              3rd hour                                                                             about 18%                                                              4th hour                                                                             about 12%                                                       ______________________________________                                    

after the 6th hour more than 90% of dipyridamole is released.

c) Filling

The pellets are mixed together in accordance with the content of activesubstance of pellet components I and II and the required dose and packedinto size 0 long capsules in a capsule filling machine.

EXAMPLE XII

Ampoules containing 5 mg of6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoicacid (Substance B)+10 mg of dipyridamole per 5 ml

    ______________________________________                                        Composition:                                                                  ______________________________________                                        (1) Dipyridamole   10 mg                                                      (2) Substance B     5 mg                                                      (3) Propyleneglycol                                                                              50 mg                                                      (4) Polyethyleneglycol                                                                            5 mg                                                      (5) Ethanol        10 mg                                                      (6) Water for injections ad                                                                       5 ml                                                      (7) Dilute HCl ad  pH 3                                                       ______________________________________                                    

The active substances are dissolved, with heating, in the solutionconsisting of ingredients (3) to (7). After checking the pH andsterilising by filtration the solution is transferred into suitableampoules and sterilised.

What is claimed is:
 1. Arylsulphonamides of formula ##STR11## wherein R₁represents a phenylalkyl, trialkylphenyl, tetramethylphenyl orpentamethylphenyl group, a thienyl group optionally substituted by ahalogen atom or an alkyl group, or a phenyl group which may bemono-substituted by a nitro group or mono- or disubstituted by a halogenatom or by an alkyl, trifluoromethyl or alkoxy group, the substituentsbeing identical or different,R₂, R₄ and R₅, which may be identical ordifferent, each represents a hydrogen atom or an alkyl group or R₂represents a hydrogen atom or an alkyl group and R₄ and R₅ togetherrepresent a carbon-carbon bond, R₃ represents a pyridyl group optionallysubstituted by an alkyl group, R₆ represents a hydroxy, alkoxy, amino,alkylamino or dialkylamino group, A represents a group of formula##STR12## wherein R₇ represents a hydrogen atom or an alkyl group, Xrepresents an alkyl-substituted imino group or an oxygen or sulphuratom, the --CHR₇ -- group being attached to the --NR₂ -- group, and Brepresents a carbon-carbon bond or a straight-chained C₁₋₄ alkylenegroup optionally substituted by one or two alkyl groups, whilst all thealkyl and alkoxy moieties mentioned hereinbefore may each contain 1 to 3carbon atoms,the enantiomers thereof, the cis- and trans-isomers thereofwhere R₄ and R₅ together represent a carbon-carbon bond, or the additionsalts thereof.
 2. Arylsulphonamides of formula I according to claim 1whereinR₁ represents a benzyl, thienyl, chlorothienyl, dichlorophenyl,dimethoxyphenyl, tetramethylphenyl or pentamethylphenyl group or aphenyl group optionally substituted by a fluorine or chlorine atom or bya nitro, methyl or trifluoromethyl group, R₂, R₄ and R₅ each represent ahydrogen atom or a methyl group or R₂ represents a hydrogen atom or amethyl group and R₄ and R₅ together represent a carbon-carbon bond, R₃represents a pyridyl group, R₆ represents a hydroxy or methoxy group, Arepresents a group of formula ##STR13## wherein R₇ represents a hydrogenatom and X represents a sulphur atom or an N-methylimino group, the--CHR₇ -- group being linked to the --NR₂ -- group, and B represents acarbon-carbon bond or a straight-chained C₂₋₄ alkylene group,theenantiomers, the cis and trans isomers where R₄ and R₅ together form acarbon-carbon bond, or the addition salts thereof.
 3. Physiologicallyacceptable addition salts of the compounds according to claims 1 or 2with inorganic or organic bases.
 4. Pharmaceutical compositioncontaining as active substance a compound according to claim 1 or aphysiologically acceptable addition salt thereof optionally togetherwith one or more inert carriers and/or diluents.
 5. Pharmaceuticalcomposition according to claim 4 suitable for the treatment andprevention of thromboembolic disorders, for the prevention ofarteriosclerosis and metastasis and for treating ischaemia, asthma andallergies.
 6. Pharmaceutical composition according to claim 4 suitablefor the treatment and prevention of diseases in whichthromboxane-mediated constriction or PGE₂ -mediated dilation of thecapillaries are involved, in order to reduce the severity of transplantrejection, to reduce renal toxicity of substances such as cyclosporin,for treating kidney diseases and for treating states of shock. 7.Pharmaceutical composition according to claim 4, or 6, characterised inthat it additionally contains as active substance a PDE inhibitor or alysing agent.